Heterocycle-substituted piperazino-dihydrothienopyrimidines

ABSTRACT

The invention relates to new dihydrothienopyrimidinesulphoxides of formula 1, as well as pharmacologically acceptable salts thereof, 
     
       
         
         
             
             
         
       
         
         wherein X is SO or SO 2 , but preferably SO, and wherein 
         R 3  denotes an optionally substituted, mono- or bicyclic, unsaturated, partially saturated or saturated heterocycle or an optionally substituted, mono- or bicyclic heteroaryl 
         and wherein R 1  and R 2  have the meanings stated in claim  1,    
         as well as pharmaceutical compositions which contain these compounds. 
       
    
     These new dihydrothienopyrimidinesulphoxides are suitable for the treatment of respiratory or gastrointestinal complaints or diseases, inflammatory diseases of the joints, skin or eyes, diseases of the peripheral or central nervous system or cancers.

The invention relates to new dihydrothienopyrimidinesulphoxides offormula 1 as well as pharmacologically acceptable salts, diastereomers,enantiomers, racemates, hydrates or solvates thereof,

wherein X is SO or SO₂, but preferably SO, and whereinR³ denotes an optionally substituted, mono- or bicyclic, unsaturated,partially saturated or saturated heterocycle or an optionallysubstituted, mono- or bicyclic heteroaryland wherein R¹ and R² have the meanings stated in claim 1,as well as pharmaceutical compositions which contain these compounds.

These new dihydrothienopyrimidinesulphoxides are suitable for thetreatment of respiratory or gastrointestinal complaints or diseases,inflammatory diseases of the joints, skin or eyes, diseases of theperipheral or central nervous system or cancers.

PRIOR ART

U.S. Pat. No. 3,318,881 and BE 663693 disclose the preparation ofdihydrothieno[3,2-d]pyrimidines which have cardiovascular and sedativeproperties. WO 2006/111549 and EP06112779.1 (EP1847543) each disclosedihydrothienopyrimidinesulphoxides according to the above formula 1,although R³ may only represent a substituted phenyl, not a heterocycleor heteroaryl.

DESCRIPTION OF THE INVENTION

Surprisingly it has been found that dihydrothienopyrimidinesulphoxidesof formula 1, wherein R³ denotes a mono- or bicyclic, unsaturated,partially saturated or saturated heterocycle or a mono- or bicyclicheteroaryl, particularly those wherein X denotes SO, are particularlysuitable for the treatment of inflammatory diseases and are superior tothe corresponding dihydrothienopyrimidinesulphoxides from the prior art.

The present invention therefore relates to compounds of formula 1

-   wherein-   X denotes SO or SO₂,-   R¹ denotes H, C₁₋₆-alkyl,-   R² is H or a group selected from among C₁₋₁₀-alkyl and C₂₋₆-alkenyl,    which may optionally be substituted by der optionally by one or more    groups selected from halogen and C₁₋₃-fluoroalkyl or which may    optionally be substituted by one or more groups selected from among    OR^(2.1), COOR^(2.1), CONR^(2.2)R^(2.3), SR^(2.1), SO—R^(2.1),    SO₂—R^(2.1), C₆₋₁₀-aryl, a het, a hetaryl, a mono- or bicyclic    C₃₋₁₀-cycloalkyl, CH₂—NR^(2.2)R^(2.3) and NR^(2.2)R^(2.3), which may    in turn optionally be substituted by one or more groups selected    from among OH, halogen, OR^(2.1), oxo, CF₃, CHF₂, CH₂F,    C₁₋₆-alkanol, C₆₋₁₀-aryl, COOR^(2.1), CH₂—NR^(2.2)R^(2.3) and    NR^(2.2)R^(2.3),    -   wherein R^(2.1) is H or a group selected from among C₁₋₆-alkyl,        C₁₋₆-alkanol, C₁₋₃-haloalkyl, mono- or bicyclic        C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl-C₁₋₆-alkylene, mono- or bicyclic        hetaryl-C₁₋₆-alkylene, het-C₁₋₆-alkylene,        C₃₋₁₀-cycloalkyl-C₁₋₆-alkylene, a mono- or bicyclic C₆₋₁₀-aryl,        a hetaryl and a het,    -   which may optionally be substituted by one or more groups        selected from among OH, O—(C₁₋₃-alkyl), halogen, C₁₋₆-alkyl and        C₆₋₁₀-aryl,    -   while R^(2.2) and R^(2.3) independently of one another denote H        or a group selected from among C₁₋₆-alkyl, mono- or bicyclic        C₃₋₁₀ cycloalkyl, C₆₋₁₀-aryl-C₁₋₆-alkylene,        hetaryl-C₁₋₆-alkylene, mono- or bicyclic C₆₋₁₀-aryl, het,        hetaryl, CO—NH₂, CO—NHCH₃, CO—N(CH₃)₂, SO₂—(C₁-C₂-alkyl),        CO—R^(2.1) and COOR^(2.1), which may optionally be substituted        by one or more groups selected from among OH, halogen,        C₁₋₆-alkyl, C₆₋₁₀-aryl and COOR^(2.1),-   while-   het is a three- to eleven-membered, mono- or bicyclic, saturated or    partially saturated, optionally anellated or optionally bridged    heterocycle, which contains 1, 2, 3 or 4 heteroatoms selected    independently of one another from among N, S or O,    -   and while-   hetaryl is a five- to eleven-membered, mono- or bicyclic, optionally    anellated heteroaryl which contains 1, 2, 3 or 4 heteroatoms    selected independently of one another from among N, S or O,-   and while-   cycloalkyl may be saturated or partially saturated,-   or-   R² denotes a mono- or polycyclic C₃₋₁₀ cycloalkyl, which may    optionally be bridged one or more times by C₁₋₃-alkyl groups and    which may optionally be substituted by a group selected from among    branched or unbranched C₁₋₆-alkanol, C₁₋₃-fluoroalkyl,    C₁₋₃-alkylene-OR^(2.1), OR^(2.1), COOR^(2.1), SO₂—NR^(2.2)R^(2.3),    het, C₆₋₁₀-aryl, C₆₋₁₀-aryl-C₁₋₆-alkylene, hetaryl-C₁₋₆-alkylene,    mono- or bicyclic C₃₋₁₀ cycloalkyl and NR^(2.2)R^(2.3), which may    optionally be substituted by one or more groups selected from among    OH, OR^(2.1), oxo, halogen, CF₃, CHF₂, CH₂F, C₆₋₁₀-aryl and    NR^(2.2)R^(2.3),-   or-   R² denotes a mono- or polycyclic C₆₋₁₀-aryl, which may optionally be    substituted by OH, SH or halogen or by one or more groups selected    from among OR^(2.1), COOR^(2.1), NR^(2.2)R^(2.3),    CH₂—NR^(2.2)R^(2.3), C₃₋₁₀-cycloalkyl, het, —C₁₋₆-alkyl,    C₁₋₃-fluoroalkyl, C₆₋₁₀-aryl-C₁₋₆-alkylene, het-C₁₋₆-alkylene,    hetaryl-C₁₋₆-alkylene, C₆₋₁₀-aryl, SO₂—CH₃, SO₂—CH₂CH₃ and    SO₂—NR^(2.2)R^(2.3), which may in turn optionally be substituted by    one or more groups selected from among OH, OR^(2.1), CF₃, CHF₂,    CH₂F, oxo, halogen, CF₃, CHF₂, CH₂F, C₆₋₁₀-aryl and NR^(2.2)R^(2.3),-   or-   R² denotes a group selected from among het and hetaryl, which may    optionally be substituted by one or more groups selected from among    halogen, OH, oxo, CF₃, CHF₂ and CH₂F or by one or more groups    selected from among OR^(2.1), C₁₋₃-alkylene-OR^(2.1), SR^(2.1),    SO—R^(2.1) and SO₂—R^(2.1), COOR^(2.1), COR^(2.1), C₁₋₆-alkanol,    C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, C₆₋₁₀-aryl-C₁₋₆-alkylene,    hetaryl-C₁₋₆-alkylene, het, hetaryl, C₁₋₃-alkylene-OR^(2.1) and    NR^(2.2)R^(2.3), which may in turn optionally be substituted by one    or more groups selected from among OH, OR^(2.1), oxo, halogen, CF₃,    CHF₂, CH₂F, C₆₋₁₀-aryl and NR^(2.2)R^(2.3),-   or wherein-   NR¹R² together denotes a heterocyclic four- to seven-membered ring    which may optionally be bridged, which contains 1, 2 or 3    heteroatoms selected from among N, O and S and which may optionally    be substituted by one or more groups selected from among OH,    OR^(2.1), C₁₋₃-alkylene-O^(R.1), oxo, halogen, C₁₋₆-alkyl,    C₆₋₁₀-aryl, COOR^(2.1), CH₂—NR^(2.2)—COO—R^(2.1),    CH₂—NR^(2.2)—CO—R^(2.1), CH₂—NR^(2.2)—CO—CH₂—NR^(2.2)R^(2.3),    CH₂—NR^(2.2)—SO₂—C₁₋₃-alkyl, CH₂—NR^(2.2)—SO₂—NR^(2.2)R^(2.3),    CH₂—NR^(2.2)—CO—NR^(2.2)R^(2.3), CO—NR^(2.2)R^(2.3),    CH₂—NR^(2.2)R^(2.3) and NR^(2.2)R^(2.3),-   and wherein-   R³ is a group selected from among a het and a hetaryl, which may    optionally be substituted by one or more groups selected from among    halogen, C₁₋₃-fluoroalkyl, CN, OH, oxo, —C₁₋₆-alkyl, —O—R^(2.1),    —COOR^(2.1), SO—R^(2.1), SO₂—R^(2.1), C₆₋₁₀-aryl,    C₁₋₃-alkylene-C₆₋₁₀-aryl, —C₁₋₃-alkylene-NR^(2.2)R^(2.3),    —NR^(2.2)R^(2.3), a C₃₋₁₀-cycloalkyl, a    C₁₋₃-alkylene-C₃₋₁₀-cycloalkyl, a het, a hetaryl,    C₁₋₃-alkylene-hetaryl, and C₁₋₃-alkylene-het, which may in turn    optionally be substituted by one or more groups selected from among    OH, halogen, —C₁₋₃-fluoroalkyl, C₁₋₆-alkyl, C₆₋₁₀-aryl,    —COO(C₁₋₃-alkyl) and O—(C₁₋₃-alkyl),-   as well as pharmacologically acceptable salts, diastereomers,    enantiomers, racemates, hydrates or solvates thereof.

The present invention further relates to the above mentioned compoundsof formula 1, wherein

-   X denotes SO or SO₂,-   R¹ denotes H-   R² is H or C₁₋₁₀-alkyl, which may optionally be substituted by one    or more groups selected from halogen and C₁₋₃-fluoroalkyl or which    may optionally be substituted by one or more groups selected from    among OR^(2.1), COOR^(2.1), CONR^(2.2)R^(2.3), SR^(2.1), SO—R^(2.1),    SO₂—R^(2.1), phenyl, a monocyclic three- to seven-membered    heterocycle, a monocyclic five- to six-membered heteroaryl, a    monocyclic C₃₋₇-cycloalkyl, CH₂—NR^(2.2)R^(2.3) and NR^(2.2)R^(2.3),    which may in turn optionally be substituted by one or more groups    selected from among OH, halogen, OR^(2.1), oxo, CF₃, CHF₂, CH₂F,    C₁₋₆-alkanol, phenyl, COOR^(2.1), CH₂—NR^(2.2)R^(2.3) and    NR^(2.2)R^(2.3),    -   while R^(2.1) is H or a group selected from among C₁₋₆-alkyl,        C₁₋₆-alkanol, C₁₋₃-haloalkyl, monocyclic C₃₋₇ cycloalkyl,        phenyl-C₁₋₆-alkylene, hetaryl-C₁₋₆-alkylene, het-C₁₋₆-alkylene,        C₃₋₇-cycloalkyl-C₁₋₆-alkylene, phenyl, a hetaryl and a het,        which may optionally be substituted by one or more groups        selected from among OH, halogen, C₁₋₆-alkyl, O—(C₁₋₃-alkyl) and        phenyl,    -   while R^(2.2) and R^(2.3) independently of one another denote H        or a group selected from among C₁₋₆-alkyl, monocyclic C₃₋₇        cycloalkyl, phenyl-C₁₋₃-alkylene, hetaryl-C₁₋₃-alkylene, phenyl,        het, hetaryl, CO—NH₂, CO—NHCH₃, CON(CH₃)₂, —CO—R^(2.1) and        —COOR^(2.1), which may optionally be substituted by one or more        groups selected from among OH, halogen, C₁₋₆-alkyl, phenyl and        COOR^(2.1),    -   while-   het is a three- to seven-membered, monocyclic, saturated or    partially saturated heterocycle or a seven- to eleven-membered,    bicyclic, saturated or partially saturated heterocycle, which    contains 1, 2, 3 or 4 heteroatoms selected independently of one    another from among N, S or O,-   and wherein    -   hetaryl is a five- to six-membered, monocyclic, aromatic        heteroaryl or a seven- to eleven-membered, bicyclic, aromatic        heteroaryl which contains in each case 1, 2, 3 or 4 heteroatoms        selected independently of one another from among N, S or O,-   and wherein    -   cycloalkyl may be saturated or partially saturated,-   or-   R² denotes a monocyclic C₃₋₇ cycloalkyl, which may optionally be    substituted by a group selected from among branched or unbranched    C₁₋₆-alkanol, C₁₋₃-fluoroalkyl, OR^(2.1), C₁₋₃-alkylene-OR^(2.1),    COOR^(2.1), SO₂—NR^(2.2)R^(2.3), het, phenyl, —C₁₋₆-alkyl,    phenyl-C₁₋₆-alkylene, hetaryl-C₁₋₆-alkylene, monocyclic C₃₋₇    cycloalkyl and NR^(2.2)R^(2.3),    -   which may optionally be substituted by one or more groups        selected from among OH, OR^(2.1), oxo, halogen, CF₃, CHF₂, CH₂F,        C₁₋₆-alkyl, phenyl and NR^(2.2)R^(2.3),-   or-   R² a phenyl which may optionally be substituted by OH, SH or halogen    or by one or more groups selected from among OR^(2.1), COOR^(2.1),    NR^(2.2)R^(2.3), CH₂—NR^(2.2)R^(2.3), C₃₋₇-cycloalkyl, het,    C₁₋₆-alkyl, C₁₋₃-fluoroalkyl, phenyl-C₁₋₆-alkylene,    het-C₁₋₆-alkylene, hetaryl-C₁₋₆-alkylene, phenyl, SO₂—CH₃,    SO₂—CH₂CH₃ and SO₂—NR^(2.2)R^(2.3),    -   which may in turn optionally be substituted by one or more        groups selected from among OH, OR^(2.1), oxo, halogen, CF₃,        CHF₂, CH₂F, C₁₋₆-alkyl, phenyl and NR^(2.2)R^(2.3),-   or-   R² denotes a group selected from among a het and a hetaryl, which    may optionally be substituted by one or more groups selected from    among halogen, OH, oxo, CF₃, CHF₂ and CH₂F or by one or more groups    selected from among OR^(2.1), —C₁₋₃-alkylene-OR^(2.1), SR^(2.1),    SO—R^(2.1), SO₂—R^(2.1), COOR^(2.1), COR^(2.1), C₁₋₆-alkanol,    C₃₋₁₀-cycloalkyl, phenyl, C₁₋₆-alkyl, phenyl-C₁₋₆-alkylene,    hetaryl-C₁₋₆-alkylene, het, hetaryl, C₁₋₆-alkanol and    NR^(2.2)R^(2.3), which may in turn optionally be substituted by one    or more groups selected from among OH, OR^(2.1), oxo, halogen, CF₃,    CHF₂, CH₂F, C₁₋₆-alkyl, phenyl and NR^(2.2)R^(2.3),-   and wherein-   R³ is a group selected from among a het and a hetaryl, which may    optionally be substituted by one or more groups selected from among    halogen, C₁₋₃-fluoroalkyl, CN, OH, oxo, —O—R^(2.1), —COOR^(2.1),    SO—R^(2.1), SO₂R^(2.1), C₆₋₁₀-aryl, C₁₋₃-alkylene-C₆₋₁₀-aryl,    —C₁₋₃-alkylene-NR^(2.2)R^(2.3), —NR^(2.2)R^(2.3), a    C₃₋₁₀-cycloalkyl, a C₁₋₃-alkylene-C₃₋₁₀-cycloalkyl, a het, a    hetaryl, C₁₋₃-alkylene-hetaryl, and C₁₋₃-alkylene-het,    -   which may in turn optionally be substituted by one or more        groups selected from among OH, halogen, —C₁₋₃-fluoroalkyl,        C₆₋₁₀-aryl, —COO(C₁₋₃-alkyl) and O—(C₁₋₃-alkyl),-   as well as pharmacologically acceptable salts, diastereomers,    enantiomers, racemates, hydrates or solvates thereof.

The invention further relates to the above mentioned compounds offormula 1, wherein

-   X denotes SO,-   R¹ denotes H-   R² is H or C₁₋₆-alkyl, which may optionally be substituted by one or    more groups selected from F, CF₃, CHF₂ or CH₂F or which may    optionally be substituted by one or more groups selected from among    OR^(2.1), COOR^(2.1), CONR^(2.2)R^(2.3), SR^(2.1), SO—R^(2.1),    SO₂—R^(2.1), phenyl, a het, a hetaryl, a monocyclic C₃₋₇-cycloalkyl,    CH₂—NR^(2.2)R^(2.3) and NR^(2.2)R^(2.3),    -   which may in turn optionally be substituted by one or more        groups selected from among OH, F, Cl, Br, CF₃, CHF₂, CH₂F,        OR^(2.1), oxo, methyl, ethyl, propyl, isopropyl, C₁₋₂-alkanol,        phenyl, COOR², CH₂—NR^(2.2)R^(2.3) and NR^(2.2)R^(2.3),    -   while R^(2.1) is H or a group selected from among methyl, ethyl,        propyl, isopropyl, monocyclic C₃₋₇ cycloalkyl,        phenyl-C₁₋₂-alkylene, hetaryl-C₁₋₂-alkylene, het-C₁₋₂-alkylene,        C₃₋₇-cycloalkyl-C₁₋₂-alkylene, phenyl, a hetaryl and a het,        which may optionally be substituted by one or more groups        selected from among OH, halogen, methyl, ethyl, propyl,        isopropyl, O-methyl, O-ethyl, O-propyl, O-isopropyl and phenyl,    -   while R^(2.2) and R^(2.3) independently of one another denote H        or a group selected from among methyl, ethyl, propyl, isopropyl,        monocyclic C₃₋₇-cycloalkyl, phenyl-C₁₋₃-alkylene,        hetaryl-C₁₋₃-alkylene, phenyl, het, hetaryl, CO—NH₂, CO—NHCH₃,        CON(CH₃)₂, SO₂—(C₁-C₂-alkyl), CO—R^(2.1) and COOR^(2.1),    -   which may optionally be substituted by one or more groups        selected from among OH, F, Cl, Br, methyl, ethyl, propyl,        isopropyl, phenyl and COOR^(2.1),-   wherein-   het is a three- to seven-membered, monocyclic, saturated or    partially saturated heterocycle which contains 1, 2 or 3 heteroatoms    selected independently of one another from among N, S or O,-   and wherein-   hetaryl is a five- to six-membered, monocyclic, aromatic heteroaryl    which contains 1, 2 or 3 heteroatoms selected independently of one    another from among N, S or O, and wherein-   cycloalkyl may be saturated or partially saturated,-   or-   R² denotes a monocyclic C₃₋₇ cycloalkyl, which may optionally be    substituted by a group selected from among branched or unbranched    C₁₋₂-alkanol, C₁₋₃-fluoroalkyl, C₁₋₃-alkylene-OR^(2.1), OR^(2.1),    COOR^(2.1), SO₂—NR^(2.2)R^(2.3), het, methyl, ethyl, propyl,    isopropyl, phenyl, phenyl-C₁₋₂-alkylene, hetaryl-C₁₋₂-alkylene,    monocyclic C₃₋₇ cycloalkyl and NR^(2.2)R^(2.3), which may optionally    be substituted by one or more groups selected from among OH,    OR^(2.1), oxo, halogen, CF₃, CHF₂, CH₂F, methyl, ethyl, propyl,    isopropyl, phenyl and NR^(2.2)R^(2.3),-   or-   R² denotes a phenyl which may optionally be substituted by OH, SH,    F, Cl or Br or by one or more groups selected from among OR^(2.1),    COOR^(2.1), NR^(2.2)R^(2.3), CH₂—NR^(2.2)R^(2.3), C₃₋₇-cycloalkyl,    het, methyl, ethyl, propyl, isopropyl, CF₃, CHF₂, CH₂F,    phenyl-C₁₋₂-alkylene, het-C₁₋₂-alkylene, hetaryl-C₁₋₂-alkylene,    phenyl, SO₂—CH₃, SO₂—CH₂CH₃ and SO₂—NR^(2.2)R^(2.3),    -   which may in turn optionally be substituted by one or more        groups selected from among OH, OR^(2.1), oxo, F, Cl, Br, CF₃,        CHF₂, CH₂F, methyl, ethyl, propyl, isopropyl, phenyl and        NR^(2.2)R^(2.3),-   or-   R² denotes a group selected from among a het and a hetaryl, which is    optionally substituted by one or more groups selected from among F,    Cl, Br, OH, oxo, CF₃, CHF₂, CH₂F and SH or by one or more groups    selected from among OR^(2.1), C₁₋₃-alkylene-OR^(2.1), SR^(2.1),    SO—R^(2.1), SO₂—R^(2.1), COOR^(2.1), COR^(2.1), C₁₋₂-alkanol,    C₃₋₁₀-cycloalkyl, phenyl, methyl, ethyl, propyl, isopropyl,    phenyl-C₁₋₂-alkylene, hetaryl-C₁₋₂-alkylene, het, hetaryl,    C₁₋₂-alkanol and NR^(2.2)R^(2.3), which may in turn optionally be    substituted by one or more groups selected from among OH, OR^(2.1),    oxo, F, Cl, Br, CF₃, CHF₂, CH₂F, C₁₋₆-alkyl, phenyl and    NR^(2.2)R^(2.3,)-   and wherein-   R³ denotes a group selected from among a saturated or partially    saturated, monocyclic three- to seven-membered heterocycle, a    saturated or partially saturated, bicyclic five- to eleven-membered    heterocycle, a monocyclic, five- to six-membered heteroaryl and a    bicyclic, seven- to eleven-membered heteroaryl,    -   which contains in each case 1, 2, 3 or 4 heteroatoms selected        independently of one another from among N, O and S    -   and which may optionally be substituted in each case by one or        more groups selected from among halogen, C₁₋₃-fluoroalkyl, CN,        OH, oxo, —C₁₋₆-alkyl, —O—R^(2.1), —COOR^(2.1), SO—R^(2.1),        SO₂—R^(2.1), C₆₋₁₀-aryl, C₁₋₃-alkylene-C₆₋₁₀-aryl,        alkylene-NR^(2.2)R^(2.3), —NR^(2.2)R^(2.3), a C₃₋₁₀-cycloalkyl,        a C₁₋₃-alkylene-C₃₋₁₀-cycloalkyl, het, a hetaryl,        C₁₋₃-alkylene-hetaryl, and C₁₋₃-alkylene-het, which may in turn        optionally be substituted by one or more groups selected from        among OH, halogen, —C₁₋₃-fluoroalkyl, C₆₋₁₀-aryl,        —COO(C₁₋₃-alkyl) and O—(C₁₋₃-alkyl),-   as well as pharmacologically acceptable salts, diastereomers,    enantiomers, racemates, hydrates or solvates thereof.

The invention preferably further relates to the above mentionedcompounds of formula 1, wherein

-   R² denotes a group according to the formula 2

-   wherein R⁵ is OH or NH₂ and-   wherein R⁴ is a group selected from among C₁₋₄-alkyl, hetaryl and    phenyl, which may optionally be substituted by one or more groups    selected from among OH, F, Br, OR^(2.1), oxo, methyl, ethyl,    C₁₋₂-alkanol, phenyl, COOR^(2.1), CH₂—NR^(2.2)R^(2.3) and    NR^(2.2)R^(2.3),    -   and wherein the other groups are as hereinbefore defined,-   as well as pharmacologically acceptable salts, diastereomers,    enantiomers, racemates, hydrates or solvates thereof.

The invention preferably also relates to the above mentioned compoundsof formula 1, wherein

-   R² is a group according to the formula 2

-   wherein R⁵ is OH or NH₂ and-   wherein R⁴ is methyl, ethyl, propyl, isopropyl-   and wherein the other groups are as hereinbefore defined,-   as well as pharmacologically acceptable salts, diastereomers,    enantiomers, racemates, hydrates or solvates thereof.

The invention preferably further relates to the above mentionedcompounds of formula 1, wherein

-   R² is a monocyclic three-, four-, five-, six- or seven-membered    cycloalkyl ring which may optionally be substituted in the spiro    position by a group selected from among —CH₂—OR^(2.1), branched or    unbranched C₂₋₆-alkylene-OR^(2.1), methyl, ethyl, propyl, isopropyl,    butyl, isobutyl, cyclopropyl, —CF₃, CHF₂, CH₂F and C₂₋₄-fluoroalkyl,    while-   R^(2.1) is selected from among methyl, ethyl, propyl, isopropyl,    butyl, isobutyl, and wherein the other groups are as hereinbefore    defined,-   as well as pharmacologically acceptable salts, diastereomers,    enantiomers, racemates, hydrates or solvates thereof.

Also particularly preferred are the above compounds of formula 1,wherein

-   R² is a phenyl which may optionally be substituted in one or both    meta positions by one or more groups selected from among methyl,    ethyl, propyl, isopropyl, cyclopropyl, F, Cl, Br, OH, OR^(2.1),    COOR^(2.1), CF₃, CHF₂, CH₂F, NH₂ and N(CH₃)₂, wherein R^(2.1) may be    H, methyl or ethyl,-   and wherein the other groups are as hereinbefore defined,-   as well as pharmacologically acceptable salts, diastereomers,    enantiomers, racemates, hydrates or solvates thereof.

Also particularly preferred are the above compounds of formula 1,wherein

-   R² is a monocyclic, saturated three-, four-, five-, six or    seven-membered heterocycle with 1, 2 or 3 heteroatoms each selected    from among N, O and S, which may optionally be substituted by one or    more groups selected from among fluorine, chlorine, bromine, CF₃,    CHF₂, CH₂F, OH, oxo and SH or by one or more groups selected from    among OR^(2.1), C₁₋₃-alkylene-OR^(2.1), SR^(2.1), SO—R^(2.1),    SO₂—R^(2.1), COOR^(2.1), COR^(2.1), C₁₋₆-alkanol, C₃₋₁₀-cycloalkyl,    phenyl, C₁₋₆-alkyl, phenyl-C₁₋₆-alkylene, hetaryl-C₁₋₆-alkylene,    het, hetaryl and NR^(2.2)R^(2.3), which may in turn optionally be    substituted by one or more groups selected from among OH, OR^(2.1),    oxo, F, Cl, CF₃, CHF₂, CH₂F, phenyl and NR^(2.2)R^(2.3),    -   wherein R^(2.1), R^(2.2) and R^(2.3) and the other groups are as        hereinbefore defined,-   as well as pharmacologically acceptable salts, diastereomers,    enantiomers, racemates, hydrates or solvates thereof.

Particularly preferred objects of the invention are the above mentionedcompounds of formula 1, wherein

-   R² is a monocyclic, saturated, six-membered heterocycle with a    heteroatom selected from among N, O and S, which may optionally be    substituted by one or more groups selected from among F, Cl, Br,    CF₃, CHF₂, CH₂F, OH, oxo, NH₂, NHCH₃, N(CH₃)₂, methyl, ethyl,    propyl, isopropyl, cyclopropyl, methoxy and ethoxy,-   and wherein the other groups are as hereinbefore defined,-   as well as pharmacologically acceptable salts, diastereomers,    enantiomers, racemates, hydrates or solvates thereof.

Particularly preferred objects of the invention are the above mentionedcompounds of formula 1, wherein

-   R² is a group selected from among piperidine or tetrahydropyran,    which may optionally be substituted by one or more groups selected    from among F, Cl, Br, OH, CF₃, CHF₂, CH₂F, NH₂, NHCH₃, N(CH₃)₂, oxo,    methyl and methoxy,-   and wherein the other groups are as hereinbefore defined,-   as well as pharmacologically acceptable salts, diastereomers,    enantiomers, racemates, hydrates or solvates thereof.

Also particularly preferred are the above compounds of formula 1,wherein

-   R³ is a monocyclic five or six-membered heteroaryl ring, which may    optionally be substituted by one or more groups selected from among    F, Cl, Br, CF₃, CHF₂, CH₂F, CN, OH, -methyl, ethyl, propyl,    isopropyl, —O-methyl, O-ethyl, —COOmethyl, —COOethyl, SO₂—(CH₃),    SO—(CH₃), SO₂—(CH₂CH₃), SO—(CH₂CH₃), phenyl, -methylene-phenyl,    -ethylene-phenyl, —NH₂, —NH(CH₃), N(CH₃)₂, -methylene-NH₂,    -methylene-NH(CH₃), -methylene-N(CH₃)₂, a C₃₋₆-cycloalkyl, a    methylene-C₃₋₆-cycloalkyl, a saturated or partially saturated, five-    to six-membered heterocycle, a five or six-membered heteroaryl,    -methylene-hetaryl, and -methylene-het, which may in turn optionally    be substituted by one or more groups selected from among OH, F, Cl,    Br, CF₃, CHF₂, CH₂F, methyl, ethyl, propyl, isopropyl, phenyl,    —COO(CH₃), —O-methyl and —O-ethyl,-   and wherein the other groups are as hereinbefore defined,-   as well as pharmacologically acceptable salts, diastereomers,    enantiomers, racemates, hydrates or solvates thereof.

Also particularly preferred are the above compounds of formula 1,wherein

-   R³ is a bicyclic 9- to 11-membered saturated, unsaturated or    partially saturated heterocycle, which may optionally be substituted    by one or more groups selected from among F, Cl, Br, CF₃, CHF₂,    CH₂F, CN, OH, -methyl, ethyl, propyl, isopropyl, —O-methyl, O-ethyl,    —COOmethyl, —COOethyl, SO₂—(CH₃), SO—(CH₃), SO₂—(CH₂CH₃),    SO—(CH₂CH₃), phenyl, -methylene-phenyl, -ethylene-phenyl, —NH₂,    —NH(CH₃), N(CH₃)₂,    -   methylene-NH₂, -methylene-NH(CH₃), -methylene-N(CH₃)₂, a        —C₃₋₆-cycloalkyl, a -methylene-C₃₋₆-cycloalkyl, a saturated,        partially unsaturated or unsaturated 5- to 6-membered        heterocycle, a 5- to 6-membered heteroaryl, -methylene-hetaryl,        and -methylene-het,-   which may in turn optionally be substituted by one or more groups    selected from among OH, F, Cl, Br, CF₃, CHF₂, CH₂F, methyl, ethyl,    propyl, isopropyl, phenyl, —COO(CH₃), —O-methyl and —O-ethyl,-   and wherein the other groups are as hereinbefore defined,-   as well as pharmacologically acceptable salts, diastereomers,    enantiomers, racemates, hydrates or solvates thereof.

Also particularly preferred are the above compounds of formula 1,wherein

-   R³ is a monocyclic five or six-membered heteroaryl ring selected    from among pyrrole, pyrazole, furan, thiophene, thiazole, imidazole,    oxazole, pyridazine, pyrimidine, pyrazine, thiadiazole, oxadiazole,    triazine, isoxazole, isothiazole and pyridine,    -   which may optionally be substituted by one or more groups        selected from among F, Cl, Br, CF₃, CHF₂, CH₂F, CN, OH, -methyl,        ethyl, propyl, isopropyl, —O-methyl, O-ethyl, —COOmethyl,        —COOethyl, SO₂—(CH₃), SO₂—(CH₂CH₃), phenyl, -methylene-phenyl,        -ethylene-phenyl, —NH₂, —NH(CH₃), N(CH₃)₂, -methylene-NH₂,        -methylene-NH(CH₃), -methylene-N(CH₃)₂, a C₃₋₆-cycloalkyl, a        methylene-C₃₋₆-cycloalkyl, a het, a hetaryl, -methylene-hetaryl,        and -methylene-het,    -   which may in turn optionally be substituted by one or more        groups selected from among OH, F, Cl, Br, CF₃, CHF₂, CH₂F,        methyl, ethyl, propyl, isopropyl, phenyl, —COO(CH₃), —O-methyl        and —O-ethyl,-   and wherein the other groups are as hereinbefore defined,-   as well as pharmacologically acceptable salts, diastereomers,    enantiomers, racemates, hydrates or solvates thereof.

The invention relates in particular to the above mentioned compounds offormula 1, wherein

-   R³ is a bicyclic 9- to 11-membered heterocycle selected from among    benzoxazole, benzodioxole, dihydrobenzodioxin, benzodioxin,    benzisoxazole, benzothiazole, benzisothiazole, thienopyrimidine,    furopyrimidine, thienopyridine, furopyridine, indole, isoindole,    quinoxaline, naphthyridine, pyridopyrazine, pyridopyrimidine,    quinoline, isoquinoline, benzimidazole,    6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine, benzothiophene,    benzofuran, quinazoline, indazole, isobenzofuran and pteridine,    -   which may optionally be substituted by one or more groups        selected from among    -   F, Cl, Br, CF₃, CHF₂, CH₂F, CN, OH, -methyl, ethyl, propyl,        isopropyl, —O-methyl, O-ethyl, —COOmethyl, —COOethyl, SO₂—(CH₃),        SO₂—(CH₂CH₃), phenyl, -methylene-phenyl, -ethylene-phenyl, —NH₂,        —NH(CH₃), N(CH₃)₂, -methylene-NH₂, -methylene-NH(CH₃),        -methylene-N(CH₃)₂, a C₃₋₆-cycloalkyl, a        methylene-C₃₋₆-cycloalkyl, a het, a hetaryl, -methylene-hetaryl,        and -methylene-het,    -   which may in turn optionally be substituted by one or more        groups selected from among OH, F, Cl, Br, CF₃, CHF₂, CH₂F,        methyl, ethyl, propyl, isopropyl, phenyl, —COO(CH₃), —O-methyl        and —O-ethyl,-   and wherein the other groups are as hereinbefore defined,-   as well as pharmacologically acceptable salts, diastereomers,    enantiomers, racemates, hydrates or solvates thereof.

The present invention relates to the compounds of formula A

but particularly to both the R-enantiomers according to formula A′ andalso the S-enantiomers according to formula A″ with respect to thestereocentre at the sulphoxide sulphur atom of the compounds of formula1,

-   wherein-   R¹ is H,-   R² is a group selected from among

-   R³ is a group is selected from among

-   as well as pharmacologically acceptable salts, diastereomers,    enantiomers, racemates, hydrates or solvates thereof.

The invention further relates to the above compounds of formula 1 aspharmaceutical compositions.

The invention further relates to the use of the above compoundsaccording to formula 1 for preparing a medicament for the treatment ofdiseases which can be treated by inhibition of the PDE4 enzyme.

The invention further relates to the use of the above compoundsaccording to formula 1 for preparing a medicament for the treatment ofrespiratory or gastrointestinal diseases or complaints, as well asinflammatory diseases of the joints, skin or eyes, cancers, and diseasesof the peripheral or central nervous system.

The invention further relates to the use of the above compoundsaccording to formula 1 for preparing a medicament for the preventionand/or treatment of respiratory or pulmonary diseases which areaccompanied by increased mucus production, inflammations and/orobstructive diseases of the respiratory tract.

The invention further relates to the use of the above compoundsaccording to formula 1 for preparing a medicament for the treatment ofinflammatory and/or obstructive diseases such as COPD, chronicsinusitis, asthma, Crohn's disease and ulcerative colitis.

The invention further relates to the use of the above compoundsaccording to formula 1 for preparing a medicament for the treatment ofinflammatory diseases of the gastrointestinal tract.

The invention further relates to the use of the above compoundsaccording to formula 1 for preparing a medicament for the prevention andtreatment of diseases of the peripheral or central nervous system suchas depression, bipolar or manic depression, acute and chronic anxietystates, schizophrenia, Alzheimer's disease, Parkinson's disease, acuteand chronic multiple sclerosis or acute and chronic pain and braindamage caused by stroke, hypoxia or cranio-cerebral trauma.

The invention further relates to pharmaceutical formulations whichcontain one or more of the above compounds according to formula 1.

The invention further relates to pharmaceutical formulations containingone or more compounds of formula 1 in combination with one or moreactive substances selected from among betamimetics, corticosteroids,other PDE4-inhibitors, EGFR-inhibitors and LTD4-antagonists,CCR3-inhibitors, iNOS-inhibitors and SYK-inhibitors.

TERMS AND DEFINITIONS USED

Unless otherwise stated, all the substituents are independent of oneanother. If for example a plurality of C₁₋₆-alkyl groups are possiblesubstituents in one group, in the case of three substituents C₁₋₆-alkyl,for example, one may represent methyl, one n-propyl and one tert-butyl,for example.

Within the scope of this application, in the definition of possiblesubstituents, these may also be represented in the form of a structuralformula. An asterisk (*) in the structural formula of the substituent isto be understood as being the linking point to the rest of the molecule.Moreover, the atom of the substituent which follows the linking point isreferred to as the atom in position number 1. Thus for example thegroups N-piperidinyl (I), 4-piperidinyl (II), 2-tolyl (III), 3-tolyl(IV) and 4-tolyl (V) are shown as follows:

If there is no asterisk (*) in the structural formula of thesubstituent, each hydrogen atom may be removed at the substituent andthe valency thus freed may serve as a binding site to the rest of amolecule, unless the linking point to the remainder of the molecule isotherwise designated or defined. Thus, for example, VI may represent2-tolyl, 3-tolyl, 4-tolyl and benzyl.

By the term “C₁₋₁₀-alkyl” (including those which are part of othergroups) are meant branched and unbranched alkyl groups with 1 to 10carbon atoms and by the term “C₁₋₆-alkyl” are meant, accordingly,branched and unbranched alkyl groups with 1 to 6 carbon atoms.“C₁₋₄-Alkyl” accordingly denotes branched and unbranched alkyl groupswith 1 to 4 carbon atoms. Alkyl groups with 1 to 4 carbon atoms arepreferred. Examples include: methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl,neo-pentyl or hexyl. The following abbreviations may optionally also beused for the above-mentioned groups: Me, Et, n-Pr, i-Pr, n-Bu, i-Bu,t-Bu, etc. Unless stated otherwise, the definitions propyl, butyl,pentyl and hexyl include all the possible isomeric forms of the groupsin question.

Thus, for example, propyl includes n-propyl and iso-propyl, butylincludes iso-butyl, sec-butyl and tert-butyl etc.

By the term “C₁₋₆-alkylene” (including those which are part of othergroups) are meant branched and unbranched alkylene groups with 1 to 6carbon atoms and by the term “C₁₋₄-alkylene” are meant branched andunbranched alkylene groups with 1 to 4 carbon atoms. Preferred arealkylene groups with 1 to 4 carbon atoms. Examples include: methylene,ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene,1,1-dimethylethylene, 1,2-dimethylethylene, pentylene,1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene,1,3-dimethylpropylene or hexylene. Unless stated otherwise, thedefinitions propylene, butylene, pentylene and hexylene include all thepossible isomeric forms of the groups in question with the same numberof carbons. Thus, for example, propyl also includes 1-methylethylene andbutylene includes 1-methylpropylene, 1,1-dimethylethylene,1,2-dimethylethylene.

If the carbon chain is substituted by a group which together with one ortwo carbon atoms of the alkylene chain forms a carbocyclic ring with 3,5 or 6 carbon atoms, the following examples of rings are also included:

By the term “C₂₋₆-alkenyl” (including those which are part of othergroups) are meant branched and unbranched alkenyl groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkenyl” are meant branched andunbranched alkenyl groups with 2 to 4 carbon atoms, provided that theyhave at least one double bond. Alkenyl groups with 2 to 4 carbon atomsare preferred. Examples include: ethenyl or vinyl, propenyl, butenyl,pentenyl or hexenyl. Unless stated otherwise, the definitions propenyl,butenyl, pentenyl and hexenyl include all the possible isomeric forms ofthe groups in question. Thus, for example, propenyl includes 1-propenyland 2-propenyl, butenyl includes 1-, 2- and 3-butenyl,1-methyl-1-propenyl, 1-methyl-2-propenyl etc.

By the term “C₂₋₆-alkenylene” (including those which are part of othergroups) are meant branched and unbranched alkenylene groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkenylene” are meant branched andunbranched alkylene groups with 2 to 4 carbon atoms. Alkenylene groupswith 2 to 4 carbon atoms are preferred. Examples of these include:ethenylene, propenylene, 1-methylethenylene, butenylene,1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene,pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene,1,2-dimethylpropenylene, 1,3-dimethylpropenylene or hexenylene. Unlessstated otherwise, the definitions propenylene, butenylene, pentenyleneand hexenylene include all the possible isomeric forms of the groups inquestion with the same number of carbons. Thus, for example, propenylalso includes 1-methylethenylene and butenylene includes1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene.

By the term “C₂₋₆-alkynyl” (including those which are part of othergroups) are meant branched and unbranched alkynyl groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkynyl” are meant branched andunbranched alkynyl groups with 2 to 4 carbon atoms, provided that theyhave at least one triple bond. Alkynyl groups with 2 to 4 carbon atomsare preferred. Examples include: ethynyl, propynyl, butynyl, pentynyl,or hexynyl. Unless stated otherwise, the definitions propynyl, butynyl,pentynyl and hexynyl include all the possible isomeric forms of thegroups in question. Thus, for example, propynyl includes 1-propynyl and2-propynyl, butynyl includes 1-, 2- and 3-butynyl, 1-methyl-1-propynyl,1-methyl-2-propynyl etc.

By the term “C₂₋₆-alkynyl” (including those which are part of othergroups) are meant branched and unbranched alkynyl groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkynyl” are meant branched andunbranched alkynyl groups with 2 to 4 carbon atoms, provided that theyhave at least one triple bond. Alkynyl groups with 2 to 4 carbon atomsare preferred. Examples include: ethynyl, propynyl, butynyl, pentynyl,or hexynyl. Unless stated otherwise, the definitions propynyl, butynyl,pentynyl and hexynyl include all the possible isomeric forms of thegroups in question. Thus for example propynyl includes 1-propynyl and2-propynyl, butynyl includes 1, 2- and 3-butynyl, 1-methyl-1-propynyl,1-methyl-2-propynyl etc.

By the term “C₂₋₆-alkynylene” (including those which are part of othergroups) are meant branched and unbranched alkynylene groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkynylene” are meant branched andunbranched alkylene groups with 2 to 4 carbon atoms. Preferred arealkynylene groups with 2 to 4 carbon atoms. Examples include:ethynylene, propynylene, 1-methylethynylene, butynylene,1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene,pentynylene, 1,1-dimethylpropynylene, 2,2-dimethylpropynylene,1,2-dimethylpropynylene, 1,3-dimethylpropynylene or hexynylene. Unlessstated otherwise, the definitions propynylene, butynylene, pentynyleneand hexynylene include all the possible isomeric forms of the groups inquestion with the same number of carbons. Thus for example propynyl alsoincludes 1-methylethynylene and butynylene includes 1-methylpropynylene,1,1-dimethylethynylene, 1,2-dimethylethynylene.

By the term “aryl” (including those which are part of other groups) aremeant aromatic ring systems with 6 or 10 carbon atoms. Examples include:phenyl or naphthyl, the preferred aryl group being phenyl. Unlessotherwise stated, the aromatic groups may be substituted by one or moregroups selected from among methyl, ethyl, iso-propyl, tert-butyl,hydroxy, fluorine, chlorine, bromine and iodine.

By the term “aryl-C₁₋₆-alkylene” (including those which are part ofother groups) are meant branched and unbranched alkylene groups with 1to 6 carbon atoms, which are substituted by an aromatic ring system with6 or 10 carbon atoms. Examples include: benzyl, 1- or 2-phenylethyl or1- or 2-naphthylethyl. Unless otherwise stated, the aromatic groups maybe substituted by one or more groups selected from among methyl, ethyl,iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

By the term “heteroaryl-C₁₋₆-alkylene” (including those which are partof other groups) are meant—even though they are already included under“aryl-C₁₋₆-alkylene”—branched and unbranched alkylene groups with 1 to 6carbon atoms, which are substituted by a heteroaryl.

A heteroaryl of this kind includes five- or six-membered heterocyclicaromatic groups or 5-10-membered, bicyclic heteroaryl rings which maycontain one, two or three heteroatoms selected from among oxygen,sulphur and nitrogen, and contain so many conjugated double bonds thatan aromatic system is formed. The following are examples of five- orsix-membered heterocyclic aromatic groups or bicyclic heteroaryl rings:

Unless otherwise stated, these heteroaryls may be substituted by one ormore groups selected from among methyl, ethyl, iso-propyl, tert-butyl,hydroxy, fluorine, chlorine, bromine and iodine.

The following are examples of heteroaryl-C₁₋₆-alkylenes:

By the term “C₁₋₆-haloalkyl” (including those which are part of othergroups) are meant branched and unbranched alkyl groups with 1 to 6carbon atoms, which are substituted by one or more halogen atoms. By theterm “C₁₋₄-alkyl” are meant branched and unbranched alkyl groups with 1to 4 carbon atoms, which are substituted by one or more halogen atoms.Alkyl groups with 1 to 4 carbon atoms are preferred. Examples include:CF₃, CHF₂, CH₂F, CH₂CF₃.

By the term “C₃₋₇-cycloalkyl” (including those which are part of othergroups) are meant cyclic alkyl groups with 3 to 7 carbon atoms. Examplesinclude: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl. Unless otherwise stated, the cyclic alkyl groups may besubstituted by one or more groups selected from among methyl, ethyl,iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

By the term “C₃₋₁₀-cycloalkyl” are also meant monocyclic alkyl groupswith 3 to 7 carbon atoms and also bicyclic alkyl groups with 7 to 10carbon atoms, or monocyclic alkyl groups which are bridged by at leastone C₁₋₃-carbon bridge.

By the term “heterocyclic rings” or “heterocycle” are meant five-, six-or seven-membered, saturated or unsaturated heterocyclic rings which maycontain one, two or three heteroatoms, selected from among oxygen,sulphur and nitrogen, while the ring may be linked to the moleculethrough a carbon atom or through a nitrogen atom, if there is one.Although included by the term “heterocyclic rings” or “heterocycles”,the term “heterocyclic non-aromatic rings” refers to five-, six- orseven-membered unsaturated rings. Examples include:

Although included by the term “heterocyclic rings” or “heterocycles”,the term “heterocyclic aromatic rings” or “heteroaryl” refers to five-or six-membered heterocyclic aromatic groups or 5-10-membered, bicyclicheteroaryl rings which may contain one, two, three or four heteroatoms,selected from among oxygen, sulphur and nitrogen, and contain so manyconjugated double bonds that an aromatic system is formed. Examples offive- or six-membered heterocyclic aromatic groups include:

Unless otherwise mentioned, a heterocyclic ring (or heterocycle) may beprovided with a keto group. Examples include:

Although covered by the term “cycloalkyl”, the term “bicycliccycloalkyls” generally denotes eight-, nine- or ten-membered bicycliccarbon rings. Examples include

Although already included by the term “heterocycle”, the term “bicyclicheterocycles” generally denotes eight-, nine- or ten-membered bicyclicrings which may contain one or more heteroatoms, preferably 1-4, morepreferably 1-3, even more preferably 1-2, particularly one heteroatom,selected from among oxygen, sulphur and nitrogen. The ring may be linkedto the molecule through a carbon atom of the ring or through a nitrogenatom of the ring, if there is one. Examples include:

Although already included by the term “aryl”, the term “bicyclic aryl”denotes a 5-10 membered, bicyclic aryl ring which contains sufficientconjugated double bonds to form an aromatic system. One example of abicyclic aryl is naphthyl.

Although already included under “heteroaryl”, the term “bicyclicheteroaryl” denotes a 5-10 membered, bicyclic heteroaryl ring which maycontain one, two, three or four heteroatoms, selected from among oxygen,sulphur and nitrogen, and contains sufficient conjugated double bonds toform an aromatic system.

Although included by the term “bicyclic cycloalkyls” or “bicyclic aryl”,the term “fused cycloalkyl” or “fused aryl” denotes bicyclic ringswherein the bridge separating the rings denotes a direct single bond.The following are examples of a fused, bicyclic cycloalkyl:

Although included by the term “bicyclic heterocycles” or “bicyclicheteroaryls”, the term “fused bicyclic heterocycles” of “fused bicyclicheteroaryls” denotes bicyclic 5-10 membered heterorings which containone, two or three heteroatoms, selected from among oxygen, sulphur andnitrogen and wherein the bridge separating the rings denotes a directsingle bond. The “fused bicyclic heteroaryls” moreover containsufficient conjugated double bonds to form an aromatic system. Examplesinclude pyrrolizine, indole, indolizine, isoindole, indazole, purine,quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran,benzothiazole, benzothiazole, benzoisothiazole, pyridopyrimidine,pteridine, pyrimidopyrimidine,

By the term “heterocyclic spiro rings” (spiro) are meant 5-10 membered,spirocyclic rings which may optionally contain one, two or threeheteroatoms, selected from among oxygen, sulphur and nitrogen, while thering may be linked to the molecule through a carbon atom or if availablethrough a nitrogen atom. Unless otherwise mentioned, a spirocyclic ringmay be provided with an oxo, methyl or ethyl group. Examples of thisinclude:

“Halogen” within the scope of the present invention denotes fluorine,chlorine, bromine or iodine. Unless stated to the contrary, fluorine,chlorine and bromine are regarded as preferred halogens.

Compounds of general formula 1 may have acid groups, mainly carboxylgroups, and/or basic groups such as e.g. amino functions. Compounds ofgeneral formula 1 may therefore be present as internal salts, as saltswith pharmaceutically usable inorganic acids such as hydrochloric acid,sulphuric acid, phosphoric acid, sulphonic acid or organic acids (suchas for example maleic acid, fumaric acid, citric acid, tartaric acid oracetic acid) or as salts with pharmaceutically usable bases such asalkali metal or alkaline earth metal hydroxides or carbonates, zinc orammonium hydroxides or organic amines such as e.g. diethylamine,triethylamine, triethanolamine, inter alia.

As mentioned previously, the compounds of formula 1 may be convertedinto the salts thereof, particularly for pharmaceutical use into thephysiologically and pharmacologically acceptable salts thereof. Thesesalts may be present on the one hand as physiologically andpharmacologically acceptable acid addition salts of the compounds offormula 1 with inorganic or organic acids. On the other hand, thecompound of formula 1 when R is hydrogen may be converted by reactionwith inorganic bases into physiologically and pharmacologicallyacceptable salts with alkali or alkaline earth metal cations ascounter-ion. The acid addition salts may be prepared for example usinghydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lacticacid, citric acid, tartaric acid or maleic acid. It is also possible touse mixtures of the above-mentioned acids. To prepare the alkali andalkaline earth metal salts of the compound of formula 1 wherein Rdenotes hydrogen, it is preferable to use the alkali and alkaline earthmetal hydroxides and hydrides, of which the hydroxides and hydrides ofthe alkali metals, particularly sodium and potassium, are preferred,while sodium and potassium hydroxide are particularly preferred.

The compounds of general formula 1 may optionally be converted into thesalts thereof, particularly for pharmaceutical use into thepharmacologically acceptable acid addition salts with an inorganic ororganic acid. Examples of suitable acids for this purpose includesuccinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid,methanesulphonic acid, lactic acid, phosphoric acid, hydrochloric acid,sulphuric acid, tartaric acid or citric acid. It is also possible to usemixtures of the above-mentioned acids.

The invention relates to the compounds in question, optionally in theform of the individual optical isomers, mixtures of the individualenantiomers or racemates, in the form of the tautomers as well as in theform of the free bases or the corresponding acid addition salts withpharmacologically acceptable acids—such as for example acid additionsalts with hydrohalic acids—for example hydrochloric or hydrobromicacid—or organic acids—such as for example oxalic, fumaric, diglycolic ormethanesulphonic acid.

The compounds according to the invention may optionally be present asracemates, but may also be obtained as pure enantiomers, i.e. in the (R)or (S) form.

The invention relates to the compounds in question, optionally in theform of the individual optical isomers, mixtures of the individualenantiomers or racemates, in the form of the tautomers as well as in theform of the free bases or the corresponding acid addition salts withpharmacologically acceptable acids—such as for example acid additionsalts with hydrohalic acids—for example hydrochloric or hydrobromicacid—or organic acids—such as for example oxalic, fumaric, diglycolic ormethanesulphonic acid.

The invention relates to the respective compounds of formula 1 in theform of the pharmacologically acceptable salts thereof as hereinbeforedescribed. These pharmacologically acceptable salts of the compounds offormula 1 may also be present in the form of their respective hydrates(e.g. monohydrated, dehydrates, etc.) as well as in the form of theirrespective solvates.

By a hydrate of the compound according to the formula 1 is meant, forthe purposes of the invention, a crystalline salt of the compoundaccording to formula 1, containing water of crystallisation.

By a solvate of the compound according to the formula 1 is meant, forthe purposes of the invention, a crystalline salt of the compoundaccording to formula 1, which contains solvent molecules (e.g. ethanol,methanol etc) in the crystal lattice.

The skilled man will be familiar with the standard methods of obtaininghydrates and solvates (e.g. recrystallisation from the correspondingsolvent in the case of solvates or from water in the case of hydrates).

Methods of Synthesis

The compounds of general formula (I) may be prepared according to thefollowing general synthesis scheme, wherein the substituents of generalformula (I) have the meanings given hereinbefore. These methods are tobe understood as being an illustration of the invention withoutrestricting it to the subject-matter thereof.

1. SYNTHESIS OF(3-FLUOROPHENYL)-5-OXO-2-(4-THIAZOL-2-YL-PIPERAZIN-1-YL)-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YL]-AMINEExample 1 1.1(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-(3-fluorophenyl)-amine(III-1)

4 g (II) are placed in 15 ml dimethylformamide, then 4.5 mldiisopropylethylamine and then 2.5 ml 3-fluorophenylamine are added. Thereaction mixture is heated to 120° C., until no further reaction takesplace, then cooled and evaporated down. The residue is mixed with water.The product is extracted with dichloromethane and purified bychromatography (silica gel, petroleum ether/ethyl acetate 80/20 to60/40). 2.6 g (III-1) are obtained as a solid. Analytical HPLC (methodA): RT=3.27 min.

1.22-chloro-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl)-(3-fluorophenyl)-amine(IV-1)

0.102 g S-(−)-1,1′-Bi-2-naphtol are placed in 0.5 ml chloroform underargon, then 0.052 ml titanium(IV)-isopropoxide and 0.064 ml of water areadded. The reaction mixture is stirred for 45 minutes at ambienttemperature. Then a suspension of 0.5 g (III-1) in 25 ml chloroform isadded. The reaction mixture is cooled to −2°/−4° C. and after 20 minutes0.323 ml tert-butylhydroperoxide 5-6 M in decane are added dropwise. Thereaction mixture is stirred further at −2/−4° C., until no furtherreaction takes place, and mixed with water. The product is extractedwith dichloromethane and purified by chromatography (silica gel,dichloromethane/methanol 100/0 to 95/5). 0.47 g (IV-1) are obtained as asolid.

Analytical HPLC-MS (method A): RT=1.16 min.

1.3(3-fluorophenyl)-[5-oxo-2-(4-thiazol-2-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-yl]-amineExample 1

0.2 g (IV-1) is placed in 3 ml dioxane, 240 μl diisopropylethylamine and0.24 g 1-thiazol-2-yl-piperazin are added. The reaction mixture isheated in the microwave at 120° C. until no further reaction takes placeand mixed with water. The precipitated solid is suction filtered andpurified by chromatography (silica gel, ethyl acetate/methanol 100/0 to80/20). 0.17 g Example 1 are obtained as a solid.

Analytical HPLC-MS (method A): RT=1.07 min.

2. SYNTHESIS OF(R)-3-METHYL-2-[5-OXO-2-(4-THIAZOL-2-YL-PIPERAZIN-1-YL)-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YLAMINO]-BUTAN-1-OLExample 2 2.1(R)-2-(2-chloro-6,7-dihydro-thieno[3,2-d]pyrimidin-4-ylamino)-3-methyl-butan-1-ol(III-2)

7.2 g 2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidin (II) are placed in36 ml dioxane, then 18 ml diisopropylethylamine and then 6.1 g(R)-(−)-2-amino-3-methyl-1-butanol are added. The reaction mixture isheated to 100° C. until no further reaction takes place, then cooled andevaporated down. The residue is treated with petroleum ether/ethylacetate 9:1 in the ultrasound bath and the solid is suction filtered anddried. 8.3 g (III-2) are obtained as a solid. Analytical HPLC (methodA): RT=2.75 min

2.2(R)-2-(2-chloro-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino)-3-methyl-butan-1-ol(IV-2)

4.1 g S-(−)-1,1′-Bi-2-naphthol are placed in 15 ml chloroform underargon, then 0.44 ml titanium(IV)-isopropoxide and 0.54 ml of water areadded. The reaction mixture is stirred for 1 hour at ambienttemperature. Then a suspension of 4.1 g (III-2) in 107 mldichloromethane is added. The reaction mixture is cooled to −2° C. andafter 30 minutes 2.7 ml tert-butylhydroperoxide 5-6 M in decane areadded dropwise. The reaction mixture is stirred further at −2° C. untilno further reaction takes place, and made basic with NH₄OH. The productis extracted with dichloromethane and purified by chromatography (silicagel, ethyl acetate/methanol 100/0 to 86/14). 2.45 g (IV-2) are obtainedas a solid.

Analytical HPLC-MS (method A): RT=0.98 min

2.3(R)-3-methyl-2-[5-oxo-2-(4-thiazol-2-yl-piperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-butan-1-olExample 2

Starting from 0.2 g (IV-2) (see 2.2) and 0.245 g1-thiazol-2-yl-piperazine 0.13 g Example 2 are prepared analogously toExample 1 (see 1.3). The reaction mixture is mixed with water and theproduct is extracted with dichloromethane and purified by chromatography(silica gel, dichloromethane/methanol 100/0 to 90/10). AnalyticalHPLC-MS (method A): RT=0.87 min.

3. SYNTHESIS OF[2-(4-BENZOXAZOL-2-YL-PIPERAZIN-1-YL)-5-OXO-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YL]-(3-FLUOROPHENYL)-AMINEExample 3

Starting from 0.2 g (IV-1) (see 1.2) and 0.287 g2-piperazin-1-yl-benzoxazole 0.31 g Example 3 are prepared analogouslyto Example 1 (see 1.3). The reaction mixture is mixed with water and theproduct is suction filtered.

Analytical HPLC-MS (method A): RT=1.23 min.

4. SYNTHESIS OF[2-(4-BENZOXAZOL-2-YL-PIPERAZIN-1-YL)-5-OXO-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YL]-(TETRAHYDROPYRAN-4-YL)-AMINEExample 5 4.1(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-(tetrahydropyran-4-yl)-amine(111-3)

0.68 g (II) are placed in 6 ml dioxane, then 1.72 mldiisopropylethylamine and then 0.6 g 4-aminotetrahydropyran are added.The reaction mixture is heated to 130° C. until no further reactiontakes place, then cooled and evaporated down. The product is treatedwith water in the ultrasound bath and the solid is suction filtered anddried. 0.66 g (III-3) are obtained. Analytical HPLC-MS (method A):RT=1.08 min.

4.2(2-chloro-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl)-(tetrahydropyran-4-yl)-amine(IV-3)

0.14 g S-(−)-1,1′-Bi-2-naphtol are placed in 5 ml chloroform underargon, then 0.072 ml titanium(IV)-isopropoxide and 0.087 ml of water areadded. The reaction mixture is stirred for 45 minutes at ambienttemperature. Then a suspension of 0.66 g (III-3) in 25 ml chloroform isadded. The reaction mixture is cooled to −10° C. and after 60 minutes0.444 ml tert-butylhydroperoxide 5-6 M in decane are added dropwise. Thereaction mixture is stirred further at −10 to −4° C., until no furtherreaction takes place, and mixed with water. The product is extractedwith dichloromethane and purified by chromatography (silica gel, ethylacetate/methanol 100/0 to 80/20). 0.42 g (IV-3) are obtained as a solid.

Analytical HPLC-MS (method A): RT=0.94 min.

4.3[2-(4-benzoxazol-2-yl-piperazin-1-yl)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]-(tetrahydropyran-4-yl)-amineExample 5

Starting from 0.2 g (IV-3) (see 4.2) and 0.315 g2-piperazin-1-yl-benzoxazole 0.3 g Example 5 are prepared and worked upanalogously to Example 3 (see 3.).

Analytical HPLC-MS (method A): RT=1.04 min.

5. SYNTHESIS OF(R)-2-{2-[4-(6-CHLORPYRIDAZIN-3-YL)-PIPERAZIN-1-YL]-5-OXO-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YLAMINO}-3-METHYLBUTAN-1-OLExample 6

Starting from 0.2 g (IV-2) (see 2.2) and 0.287 g3-chloro-6-piperazin-1-yl-pyridazine, 0.257 g Example 6 are prepared andworked up analogously to Example 3 (see 3.).

Analytical HPLC-MS (method A): RT=0.98 min.

6. SYNTHESIS OF{2-[4-(6-CHLORPYRIDAZIN-3-YL)-PIPERAZIN-1-YL]-5-OXO-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YL}-(3-FLUOROPHENYL)-AMINEExample 7

Starting from 0.2 g (IV-1) (see 1.2) and 0.28 g3-chloro-6-piperazin-1-yl-pyridazine, 0.31 g Example 7 are preparedanalogously to Example 3 (see 3.).

Analytical HPLC-MS (method A): RT=1.12 min.

7. SYNTHESIS OF(R)-2-[2-(4-BENZOXAZOL-2-YL-PIPERAZIN-1-YL)-5-OXO-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YLAMINO]-3-METHYLBUTAN-1-OLExample 10

Starting from 0.2 g (IV-2) (see 2.2) and 0.313 g2-piperazin-1-yl-benzoxazole 0.16 g Example 10 are prepared analogouslyto Example 1 (see 1.3). The reaction mixture is mixed with water and theproduct is extracted with dichloromethane and purified by chromatography(silica gel, ethyl acetate/methanol 100/0 to 80/20).

Analytical HPLC-MS (method A): RT=1.06 min.

8. SYNTHESIS OF(1-{2-[4-(5-CHLOROPYRIDIN-2-YL)-PIPERAZIN-1-YL]-5-OXO-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YLAMINO}-CYCLOPROPYL)-METHANOLExample 13 8.1 tert-butyl (1-hydroxymethylcyclopropyl)-carbamidate

1 g 1-(BOC-amino)-cyclopropanecarboxylic acid is dissolved in 20 mldimethoxyethane and cooled to −70° C. Then 0.65 ml N-methylmorpholineare added and 0.71 ml isobutyl chloroformate in 5 ml dimethoxyethane isadded dropwise. The reaction mixture is heated to −5° C. The precipitateis suction filtered. The eluate is cooled to −15° C. and 0.303 g sodiumborohydride are slowly added. The reaction mixture is then stirred for30 minutes at ambient temperature, mixed with water and the product isextracted with dichloromethane. The organic phase is dried andevaporated to dryness. 1.04 g product are obtained as a solid.

¹H NMR (400 MHz, DMSO): 1.36 (9H, s); 0.61 (2H, t); 0.52 (2H, t).

8.2 1-aminocyclopropanemethanol

1.04 g tert-butyl (1-hydroxymethylcyclopropyl)-carbamidate are placed in5 ml dioxane. 2.5 ml HCl in dioxane (4 mol/l) are added dropwise. Thereaction mixture is stirred for 15 h at ambient temperature. The solventis evaporated down by half and the precipitated solid is suctionfiltered. 0.5 g product are obtained as the hydrochloride.

¹H NMR (400 MHz, DMSO): 5.27 (1H, t); 0.91 (2H, t); 0.71 (2H, t).

8.3[1-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-cyclopropyl]-methanol(III-4)

1.4 g (II) are placed in 10 ml dioxane, first 3.6 mldiisopropylethylamine, then 1 g of 1-aminocyclopropanemethanol (see 8.2)are added. The reaction mixture is heated to 160° C. until no furtherreaction takes place, then cooled and evaporated down. The residue istreated with cyclohexane/ethyl acetate (8:2) in the ultrasound bath andthe solid is suction filtered and dried. 1.24 g (III-4) are obtained asa solid.

Analytical HPLC-MS (method A): RT=1.01 min.

8.4[1-(2-chloro-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino)-cyclopropyl]-methanol(IV-4)

0.28 g S-(−)-1,1′-Bi-2-naphtol are placed in 20 ml chloroform underargon, then 0.14 ml titanium(IV)-isopropoxide and 0.17 ml of water areadded. The reaction mixture is stirred for 1 hour at ambienttemperature. Then a suspension of 1.2 g (III-4) in 40 ml dichloromethaneand 2 ml of methanol is added. The reaction mixture is cooled to −5° C.and after 30 minutes 0.91 ml tert-butylhydroperoxide 5-6 M in decane areadded dropwise. The reaction mixture is stirred further at −5° C. untilno further reaction takes place, and made basic with NH₄OH. The aqueousphase is washed with dichloromethane and freeze-dried. 1 g (IV-4) isobtained as a solid. Analytical HPLC-MS (method A) RT=0.85 min.

8.5(1-{2-[4-(5-Chloropyridin-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino}-cyclopropyl)-methanolExample 13

0.1 g (IV-4) (see 8.4) is placed in 3 ml N-methyl-2-pyrrolidone, then182 μl diisopropylethylamine and 0.08 g1-(5-chloropyridin-2-yl)-piperazine are added. The reaction mixture isheated in the microwave at 120° C., until no further reaction takesplace. The product is purified by chromatography (preparative HPLC,method A).

Analytical HPLC-MS (method B): RT=1.09 min.

9. SYNTHESIS OF{2-[4-(5-CHLOROPYRIDIN-2-YL)-PIPERAZIN-1-YL]-5-OXO-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YL}-TETRAHYDROPYRAN-4-YL)-AMINEExample 14

Starting from 0.11 g (IV-3) (see 4.2) and 0.083 g1-(5-Chloropyridin-2-yl)-piperazine 0.14 g Example 14 are prepared andpurified analogously to Example 13 (see 8.5).

Analytical HPLC-MS (method B): RT=1.14 min.

10. SYNTHESIS OF{2-[4-(3-DIMETHYLAMINOPYRIDAZIN-4-YL)-PIPERAZIN-1-YL]-5-OXO-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YL}-(3-FLUOROPHENYL)-AMINETRIFLUOROACETATE Example 15 10.1 3,4,6-trichloropyridazine

44 g 3,6-dichloropyridazine and 22 g aluminium trichloride are heated to140° C. At this temperature 10.6 l chlorine are piped into the reactionmixture over 4 hours. After cooling the product is extracted withtoluene, washed with a 10% sodium chloride solution and distilled(bp=127-129° C.). 44.1 g of product are obtained.

10.2 3,6-dichloro-4-piperazin-1-yl-pyridazine

18 g 3,4,6-trichloro-pyridazine and 34 g piperazine are suspended in 100ml of ethanol and stirred for 30 minutes at ambient temperature. Theprecipitated solid is suction filtered. 500 ml of water are added to themother liquor and the precipitated product is suction filtered. 14 g ofproduct are obtained as a solid. M.p=111-115° C.

10.3 (6-chloro-4-piperazin-1-yl-pyridazin-3-yl)-dimethylamine

23 g 3,6-dichloro-4-piperazin-1-yl-pyridazine and 45 g dimethylamine aresuspended in 200 ml of methanol and autoclaved for 4 hours at 100° C.The reaction mixture is evaporated to dryness and the product isextracted with chloroform and washed with sodium hydroxide solution. Thehydrochloride is precipitated with an ethereal HCl solution. 27 gproduct are obtained. M.p=291° C.

10.4 dimethyl-(4-piperazin-1-yl-pyridazin-3-yl)amine (V-1)

9.4 g (6-chloro-4-piperazin-1-yl-pyridazin-3-yl)-dimethylaminehydrochloride and 7.3 g sodium acetate are suspended in 150 ml ofmethanol and hydrogenated with 1 g Pd/C 10% at ambient temperature. Thecatalyst is suction filtered, the filtrate is evaporated to dryness andthe product is extracted with chloroform and washed with sodiumhydroxide solution. The hydrochloride is precipitated with an etherealHCl solution. 7 g (V-1) are obtained.

M.p=335° C.

10.5{2-[4-(3-dimethylaminopyridazin-4-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl}-(3-fluorophenyl)-amineExample 15

(IV-1) (see 1.2) (0.1 mmol) is placed in 750 μl ofN-methyl-2-pyrrolidone (NMP) and 50 μl diisopropylethylamine, combinedwith a solution of dimethyl-(4-piperazin-1-yl-pyridazin-3-yl)-amine (0.1mmol, see 10.4) in 400 μl NMP and heated to 120° C. for 30 min in themicrowave. Then 600 μL DMF are added, the reaction solution is purifiedby chromatography (preparative HPLC-MS, method A) and the productfractions are freeze-dried. Example 15 is obtained as thetrifluoroacetate. Analytical HPLC-MS (method C): RT=1.61 min.

11. SYNTHESIS OF6-CHLORO-4-{4-[4-(3-FLUOROPHENYLAMINO)-5-OXO-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-2-YL]-PIPERAZIN-1-YL}-PYRIDAZIN-3-OLExample 16 11.1 (6-chloro-4-piperazin-1-yl-pyridazin-3-yloxy)-ethanol

23 g of 3,6-dichloro-4-piperazin-1-yl-pyridazine (see 10.2) aresuspended in 100 ml ethyleneglycol and added dropwise to a suspension of2.3 g sodium in 100 ml ethylenglycol getropft. The reaction mixture isheated to 100° C. for 3 hours and evaporated to dryness. The residue issuspended in acetonitrile and the solid is suction filtered. The motherliquor is evaporated to dryness, the product is extracted withdichloromethane and washed with conc. NaOH. The product is suspended inethanol and precipitated as the fumarate with fumaric acid. 13 g productare obtained. M.p=179° C.

11.2 6-chloro-4-piperazin-1-yl-pyridazin-3-ol (V-2)

15 g (6-chloro-4-piperazin-1-yl-pyridazin-3-yloxy)-ethanol fumarate aresuspended in 90 ml hydrobromic acid (48%). The reaction mixture isstirred for 1 hour at reflux temperature and evaporated to dryness. 19 gproduct are obtained as the hydrobromide. M.p=35° C.

11.36-chloro-4-{4-[4-(3-fluorophenylamino)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-2-yl]-piperazin-1-yl}-pyridazin-3-olExample 16

Starting from (IV-1) (see 1.2) and (V-2) (see 11.2) Example 16 isprepared and purified analogously to Example 15 (see 10.5). AnalyticalHPLC-MS (method C): RT=1.86 min.

12. SYNTHESIS OF(2-{4-[6-(2-ETHOXYETHOXY)-PYRIDAZIN-3-YL]-PIPERAZIN-1-YL}-5-OXO-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YL)-(3-FLUOROPHENYL)-AMINETRIFLUOROACETATE Example 17 12.13-ethoxyethoxy-6-piperazin-1-yl-pyridazine (V-3)

18 g 3-chloro-6-piperazin-1-yl-pyridazine and 30 g potassium hydroxidein 30 ml of water are suspended in 180 ml ethylglycol and refluxed for 4hours with stirring. The reaction mixture is evaporated to dryness. Theproduct is extracted with diethyl ether, washed with a concentratedpotassium carbonate solution and distilled (bp=190° C.). 18 g (V-3) areobtained.

12.2(2-{4-[6-(2-ethoxyethoxy)-pyridazin-3-yl]-piperazin-1-yl}-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl)-(3-fluorophenyl)-amineExample 17

Starting from (IV-1) (see 1.2) and (V-3) (see 12.1) Example 17 isprepared and purified as the trifluoroacetate analogously to Example 15(see 10.5).

Analytical HPLC-MS (method C): RT=1.66 min.

13. SYNTHESIS OF(3-FLUOROPHENYL)-[5-OXO-2-(4-PYRIDAZIN-4-YL-PIPERAZIN-1-YL)-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YL]-AMINETRIFLUOROACETATE Example 18 13.1 4-piperazin-1-yl-pyridazine (V-4)

9.3 g 3,6-dichloro-4-piperazin-1-yl-pyridazine (see 10.2) and 6.5 gsodium acetate are suspended in 100 ml of methanol and hydrogenated with1 g Pd/C 10% and ambient temperature. The catalyst is suction filteredand the filtrate is evaporated to dryness. The product is extracted withchloroform, washed with sodium hydroxide solution and precipitated asthe hydrochloride with an ethereal HCl solution. 8.6 g (V-4) areobtained. M.p>300° C.

13.2 (3-fluorophenyl)-[5-oxo-2-(4-pyridazin-4-yl-piperazin-1-yl)6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]-amine Example 18

Starting from (IV-1) (see 1.2) and (V-4) (see 13.1) Example 18 isprepared and purified as the trifluoroacetate analogously to Example 15(see 10.5).

Analytical HPLC-MS (method C): RT=1.54 min.

14. SYNTHESIS OF(R)-2-{2-[4-(4-METHOXY-1-METHYL-1H-BENZIMIDAZOL-2-YL)-PIPERAZIN-1-YL]-5-OXO-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YLAMINO}-3-METHYLBUTAN-1-OLTRIFLUOROACETATE Example 23 14.1 tert-butyl(3-methoxy-2-nitrophenyl)-carbamidate

10 g 3-methoxy-2-nitrobenzoic acid and 7 ml triethylamine are placed in100 ml tert-butanol and 11 ml diphenylphosphorylazide are addeddropwise. The reaction mixture is then stirred for 6 hours at refluxtemperature and evaporated to dryness. The product is extracted withethyl acetate, washed with a 10% citric acid, a saturated sodiumhydrogen carbonate and a saturated sodium chloride solution. 12.4 gproduct are obtained as a solid. M.p=90° C.

14.2 tert-butyl (3-methoxy-2-nitrophenyl)-methyl-carbamidate

12.2 g tert-butyl (3-methoxy-2-nitrophenyl)-methyl-carbamidate areplaced in 80 ml dimethylformamide and cooled to 0° C. 2.4 g sodiumhydride (50% ig in mineral oil) are slowly added. The reaction mixtureis stirred for 30 minutes at 0° C. Then 3.1 ml methyl iodide are addeddropwise. The reaction mixture is stirred for 2 hours at ambienttemperature and mixed with water. The product is extracted with ethylacetate. 12.5 g product are obtained as an oil.

14.3 (3-methoxy-2-nitrophenyl)-methylamine

12.5 g tert-butyl (3-methoxy-2-nitrophenyl)-methyl-carbamidate and 78 mlhydrochloric acid (4 M) are suspended in 300 ml of ethyl acetate andheated to 60° C. for 5 hours. The reaction mixture is evaporated todryness, the residue is combined with a saturated sodium hydrogencarbonate solution and the product is extracted with ethyl acetate. 7.5g product are obtained as a solid. M.p=58-59° C.

14.4 3-methoxy-N¹-methylbenzol-1,2-diamine

7.4 g (3-methoxy-2-nitrophenyl)-methylamine are suspended in 150 ml ofethyl acetate and hydrogenated with 1 g Pd/C 10% at a pressure of 50 psiand ambient temperature. After 4.5 hours the catalyst is suctionfiltered and the filtrate is evaporated to dryness. 5.9 g of the productare obtained as an oil.

14.5 4-methoxy-1-methyl-1,3-dihydrobenzimidazol-2-one

5.9 g 3-methoxy-N1-methylbenzol-1,2-diamine are suspended in 70 ml oftetrahydrofuran and 6.3 g N,N′-carbonyldiimidazole are added. Thereaction mixture is stirred for 5 hours at ambient temperature, mixedwith water and the product is extracted with ethyl acetate. 3.9 gproduct are obtained as a solid.

14.6 2-chloro-4-methoxy-1-methyl-1H-benzimidazole

3.7 g 4-methoxy-1-methyl-1,3-dihydrobenzimidazol-2-one are suspended in15 ml phosphorus oxychloride. The reaction mixture is stirred for 3hours at reflux temperature, slowly combined with ice water and madealkaline with conc. Ammonia. The precipitated product is suctionfiltered. 3.6 g product are obtained as a solid. M.p=118-119° C.

14.7 4-methoxy-1-methyl-2-piperazin-1-yl-1-benzimidazole (V-5)

2 g of 2-chloro-4-methoxy-1-methyl-1H-benzimidazole and 4.4 g piperazineare suspended in 20 ml n-butanol and stirred for 5 hours at refluxtemperature. The reaction mixture is evaporated to dryness and theproduct is purified by chromatography (silica gel,dichloromethane/methanol 10:1). 1.6 g (V-5) are obtained as a solid.M.p=147° C.

14.8(R)-2-{2-[4-(4-methoxy-1-methyl-1H-benzimidazol-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino}-3-methylbutan-1-olExample 23

Starting from (IV-2) (see 2.2) and (V-5) (see 14.7) Example 23 isprepared and purified as the trifluoroacetate analogously to Example 15(see 10.5).

Analytical HPLC-MS (method C): RT=1.5 min.

15. SYNTHESIS OF(R)-2-{2-[4-(7-ETHYL-6,7,8,9-TETRAHYDRO-5H-PYRAZINO[2,3-D]AZEPIN-2-YL)-PIPERAZIN-1-YL]-5-OXO-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YLAMINO}-3-METHYLBUTAN-1-OLTRIFLUOROACETATE Example 24 15.12-chloro-7-ethyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine

26.5 g 7-ethyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepin-2-ylamine(U.S. Pat. No. 4,409,220) are suspended in 130 ml conc. Hydrochloricacid, combined with 0.1 g copper(I) bromide and cooled to −5° C. Asuspension of 11 g sodium nitrite in 14 ml of water is slowly addeddropwise. The reaction mixture is stirred for 15 hours at ambienttemperature and evaporated almost to dryness. The residue is slowlyadded to ice water and potassium carbonate. The product is extractedwith dichloromethane and precipitated as the hydrochloride with anethereal HCl solution. 14.3 g product are obtained. M.p=258-262° C.

15.27-ethyl-2-piperazin-1-yl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine(V-6)

3 g 2-chloro-7-ethyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine arecombined with 23.3 g piperazine and heated for 5 hours to 145° C. Excesspiperazine is distilled off and the residue is treated withdichloromethane and methanol. Any precipitated product is suctionfiltered and purified by chromatography (Alox,dioxane/toluene/methanol/NH₄OH 50/20/20/2). 1.95 g of product areobtained.

15.3(R)-2-{2-[4-(7-ethyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepin-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5⁴-thieno[3,2-d]pyrimidin-4-ylamino}-3-methylbutan-1-olExample 24

Starting from (IV-2) (see 2.2) and (V-6) (see 15.2) Example 24 isprepared and purified as the trifluoroacetate analogously to Example 15(see 10.5).

Analytical HPLC-MS (method C): RT=1.38 min.

16. SYNTHESIS OF(R)-3-METHYL-2-[5-OXO-2-(4-PYRIMIDIN-4-YL-PIPERAZIN-1-YL)-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YLAMINO]-BUTAN-1-OLTRIFLUOROACETATE Example 28

Starting from (IV-2) (see 2.2) and 4-piperazin-1-yl-pyrimidin (J. Org.Chem. 1953, 1484) Example 28 is prepared and purified as thetrifluoroacetate analogously to Example 15 (see 10.5). AnalyticalHPLC-MS (method C): RT=1.31 min.

17. SYNTHESIS OF4-{4-[4-((R)-1-HYDROXYMETHYL-2-METHYLPROPYLAMINO)-5-OXO-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-2-YL]-PIPERAZIN-1-YL}-PYRIDIN-2-OLExample 29 17.1 4-(1-oxypyridin-4-yl)-piperazine-1-BOC

3 g 4-Chloropyridine-N-oxide and 13.2 g piperazine-1-BOC are heated to90° C. for 4 hours. The product is purified by chromatography (silicagel, dichloromethane/methanol/ammonia 90/10/1). 2.9 g product areobtained as a solid.

17.2 4-(2-hydroxypyridin-4-yl)piperazine-1-BOC

1.75 g 4-(1-oxypyridin-4-yl)-piperazin-1-BOC are suspended in 15 mlacetic anhydride and heated to 150° C. for 24 h. The reaction mixture isevaporated to dryness and the product is purified by chromatography(silica gel, ethyl acetate/methanol/ammonia 95/5/0.5). 0.51 g productare obtained as a solid

17.3 4-piperazin-1-yl-pyridin-2-ol (V-7)

0.51 g 4-(2-hydroxypyridin-4-yl)-piperazine-1-BOC and 2 mltrifluoroacetic acid are suspended in 15 ml dichloromethane and stirredfor 2 hours at ambient temperature. The reaction mixture is evaporatedto dryness. 1 g (V-7) are obtained as an oil.

¹H NMR (400 MHz, DMSO): 7.30 (1H, d); 5.99 (1H, dd); 5.34 (1H, d).

17.44-{4-[4-((R)-1-hydroxymethyl-2-methylpropylamino)-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-2-yl]-piperazin-1-yl}-pyridin-2-olExample 29

Starting from (IV-2) (see 2.2) and (V-7) (see 17.3) Example 29 isprepared and purified analogously to Example 15 (see 10.5). AnalyticalHPLC-MS (method C): RT=1.37 min.

18. SYNTHESIS OF(R)-3-METHYL-2-[5-OXO-2-(4-PYRIDIN-4-YL-PIPERAZIN-1-YL)-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YLAMINO]-BUTAN-1-OLTRIFLUOROACETATE Example 32

Starting from (IV-2) (see 2.2) and 1-pyridin-4-yl-piperazine Example 32is prepared and purified as the trifluoroacetate analogously to Example15 (see 10.5).

Analytical HPLC-MS (method C): RT=1.33 min.

19. SYNTHESIS OF(R)-2-{2-[4-(3-DIMETHYLAMINOPYRIDAZIN-4-YL)-PIPERAZIN-1-YL]-5-OXO-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YLAMINO}-3-METHYLBUTAN-1-OLTRIFLUOROACETATE Example 36

Starting from (IV-2) (see 2.2) and (V-1) (see 10.4) Example 36 isprepared and purified as the trifluoroacetate analogously to Example 15(see 10.5).

Analytical HPLC-MS (method C): RT=1.37 min.

20. SYNTHESIS OF6-CHLORO-4-{4-[4-((R)-1-HYDROXYMETHYL-2-METHYLPROPYLAMINO)-5-OXO-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-2-YL]-PIPERAZIN-1-YL}-PYRIDAZIN-3-OLExample 37

Starting from (IV-2) (see 2.2) and (V-2) (see 11.2) Example 37 isprepared and purified analogously to Example 15 (see 10.5). AnalyticalHPLC-MS (method C): RT=1.55 min.

21. SYNTHESIS OF(R)-2-(2-{4-[6-(2-ETHOXYETHOXY)-PYRIDAZIN-3-YL]-PIPERAZIN-1-YL}-5-OXO-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YLAMINO)-3-METHYLBUTAN-1-OLTRIFLUOROACETATE Example 38

Starting from (IV-2) (see 2.2) and (V-3) (see 12.1) Example 38 isprepared and purified as the trifluoroacetate analogously to Example 15(see 10.5). Analytical HPLC-MS (method C): RT=1.45 min.

22. SYNTHESIS OF(R)-3-METHYL-2-[5-OXO-2-(4-PYRIDAZIN-4-YL-PIPERAZIN-1-YL)-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YLAMINO]-BUTAN-1-OLTRIFLUOROACETATE

Example 39

Starting from (IV-2) (see 2.2) and (V-4) (see 13.1) Example 39 isprepared and purified as the trifluoroacetate analogously to Example 15(see 10.5).

Analytical HPLC-MS (method C): RT=0.56 min.

23. SYNTHESIS OF{1-[5-OXO-2-(4-PYRIMIDIN-4-YL-PIPERAZIN-1-YL)-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YLAMINO]-CYCLOPROPYL}-METHANOLTRIFLUOROACETATE Example 55

Starting from (IV-4) (see 8.4) and 4-piperazin-1-yl-pyrimidine (J. Org.Chem. 1953, 1484) Example 55 is prepared and purified as thetrifluoroacetate analogously to Example 15 (see 10.5). AnalyticalHPLC-MS (method C): RT=1.29 min.

24 SYNTHESIS OF{1-[5-OXO-2-(4-PYRIDIN-4-YL-PIPERAZIN-1-YL)-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YLAMINO]-CYCLOPROPYL}-METHANOLTRIFLUOROACETATE Example 58

Starting from (IV-4) (see 8.4) and 1-pyridin-4-yl-piperazine Example 58is prepared and purified as the trifluoroacetate analogously to Example15 (see 10.5).

Analytical HPLC-MS (method C): RT=1.29 min.

25. SYNTHESIS OF(S)-1-METHYL-5-[5-OXO-2-(4-PYRIMIDIN-4-YL-PIPERAZIN-1-YL)-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YLAMINO]-PIPERIDIN-2-ONETRIFLUOROACETATE Example 71 25.1 (S)-5-dibenzylaminopiperidin-2-one

0.600 g 4-(6)-amino-delta-valerolactam hydrochloride, 0.970 mlbenzylbromide and 1.5 g sodium hydrogen carbonate are suspended in 30 mlof ethanol. The reaction mixture is then stirred for 8 hours at 80° C.and then evaporated to dryness. The residue is suspended in water andthe product is extracted with dichloromethane and purified bychromatography (silica gel, dichloromethane/methanol 100/0 to 95/5).0.500 g of the product are obtained as an oil. Analytical HPLC-MS(method A): RT=1.01 min.

25.2 (S)-5-dibenzylamino-1-methylpiperidin-2-one

0.500 g (S)-5-dibenzylaminopiperidin-2-one are suspended in 15 ml oftetrahydrofuran. 0.175 g potassium-tert-butoxide are added while coolingwith the ice bath. The reaction mixture is then stirred for 30 minutesat ambient temperature. While cooling with the ice bath 0.095 ml methyliodide are added. The reaction mixture is then stirred for 48 hours atambient temperature and then combined with a saturated NaCl solution.The product is extracted with ethyl acetate. 0.450 g of the product areobtained as an oil.

Analytical HPLC-MS (method A): RT=1.07 min.

25.3 (S)-5-amino-1-methylpiperidin-2-one

0.450 g (S)-5-dibenzylamino-1-methylpiperidin-2-one are suspended in 25ml of methanol and hydrogenated with 0.150 g Pd/C 10% at a pressure of 3bar and a temperature of 60° C. After 16 hours the catalyst is suctionfiltered and the filtrate is evaporated to dryness. 0.190 g of theproduct are obtained as an oil. ¹H NMR (400 MHz, DMSO): 2.76 (3H, s).

25.4(S)-5-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-1-methylpiperidin-2-one(III-5)

0.27 g (II) are placed in 3 ml dioxane, then 0.45 mldiisopropylethylamine and 0.25 g (S)-5-amino-1-methylpiperidin-2-one areadded. The reaction mixture is heated to 130° C. until no furtherreaction takes place, then cooled and evaporated down. The product isextracted with dichloromethane and purified by chromatography(preparative HPLC, method B). 0.26 g (III-5) are obtained as a solid.Analytical HPLC-MS (method A): RT=1.06 min.

25.5(S)-5-(2-chloro-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino)-1-methylpiperidin-2-one(IV-5)

0.04 g S-(−)-1,1′-Bi-2-naphtol are placed in 5 ml chloroform underargon, then 0.02 ml titanium(IV)-isopropoxide and 0.025 ml of water areadded. The reaction mixture is stirred for 1 hour at ambienttemperature. Then a suspension of 0.2 g (III-5) in 4 ml dichloromethaneis added. The reaction mixture is cooled to −5° C. and after 20 minutes0.12 ml tert-butylhydroperoxide 5-6 M in decane are added dropwise. Thereaction mixture is stirred further at −5° C. until no further reactiontakes place, and made basic with NH₄OH. The product is extracted withdichloromethane and purified by chromatography (silica gel, ethylacetate/methanol 100/0 to 60/40). 0.09 g (IV-5) are obtained as a solid.

Analytical HPLC-MS (method A): RT=0.83 min.

25.6 (S)-1-methyl-5-[5-oxo-2-(4-pyrimidin-4-yl-piperazin-1-yl)6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-ylamino]-piperidin-2-oneExample 71

Starting from (IV-5) (see 25.5) and 4-piperazin-1-yl-pyrimidine (J. Org.Chem. 1953, 1484) Example 71 is prepared and purified as thetrifluoroacetate analogously to Example 15 (see 10.5). AnalyticalHPLC-MS (method C): RT=1.28 min.

26. SYNTHESIS OF{2-[4-(5-FLUORO-1-METHYL-1H-BENZIMIDAZOL-2-YL)-PIPERAZIN-1-YL]-5-OXO-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YL}-(TETRAHYDROPYRAN-4-YL)-AMINEExample 87 26.1 (4-fluoro-2-nitrophenyl)-methylamine

7.3 g 1,4-difluoro-2-nitrobenzene are slowly added to 30 ml of a 40%aqueous methylamine solution while cooling with ice and the reactionmixture is stirred for 1 hour at ambient temperature. The precipitatedproduct is suction filtered and recrystallised from water and ethanol.6.3 g product are obtained as a solid. M.p=74-76° C.

26.2 4-fluoro-N¹-methylbenzene-1,2-diamine

6.2 g (4-fluoro-2-nitrophenyl)-methylamine are suspended in 200 ml ofethyl acetate and hydrogenated with 1 g Raney nickel at a pressure of 5bar and ambient temperature. After 4.5 hours the catalyst is suctionfiltered and the filtrate is evaporated to dryness. 3.9 g product areobtained as an oil.

26.3 5-fluoro-1-methyl-1,3-dihydrobenzimidazol-2-one

6 g 4-fluoro-N1-methylbenzene-1,2-diamine are suspended in 200 ml oftetrahydrofuran and 7.1 g N,N′-carbonyldiimidazole are added. Thereaction mixture is stirred for 48 hours at ambient temperature and theprecipitated product is suction filtered and recrystallised fromdioxane. 3.9 g product are obtained as a solid. M.p=207° C.

26.4 2-chloro-5-fluoro-1-methyl-1H-benzimidazole

3.9 g 5-fluoro-1-methyl-1,3-dihydro-benzimidazol-2-one are suspended in80 ml phosphorus oxychloride and the reaction mixture is stirred for 2hours at reflux temperature. 50 ml diethylaniline are added. Thereaction mixture is stirred for a further 10 minutes at refluxtemperature and slowly combined with ice water. The product is extractedwith dichloromethane and purified by chromatography (silica gel,cyclohexane, methylene chloride/acetone 20/1). 1.4 g product areobtained as a solid. M.p=138-141° C.

26.5 5-fluoro-1-methyl-2-piperazin-1-yl-1H-benzimidazole (V-8)

0.7 g 2-chloro-5-fluoro-1-methyl-1H-benzimidazole and 1.3 g piperazineare suspended in 10 ml n-butanol and stirred for 48 hours at ambienttemperature. The reaction mixture is evaporated to dryness and theproduct is purified by chromatography (aluminium oxide, methylenechloride/methanol 10/1). 0.73 g (V-8) are obtained as a solid. ¹H NMR(400 MHz, DMSO): 6.9 (1H, t); 3.6 (3H, s).

26.6{2-[4-(5-fluoro-1-methyl-1H-benzoimidazol-2-yl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl}-(tetrahydropyran-4-yl)-amineExample 87

Starting from (IV-3) (see 4.2) and (V-8) (see 26.5) Example 87 isprepared and purified analogously to Example 15 (see 10.5). AnalyticalHPLC-MS (method C): RT=1.48 min.

27. SYNTHESIS OF[5-OXO-2-(4-PYRIDIN-4-YL-PIPERAZIN-1-YL)-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YL]-(TETRAHYDROPYRAN-4-YL)-AMINETRIFLUOROACETATE Example 96

Starting from (IV-3) (see 4.2) and 1-pyridin-4-yl-piperazine Example 96is prepared and purified as the trifluoroacetate analogously to Example15 (see 10.5). Analytical HPLC-MS (method C): RT=1.32 min.

28. SYNTHESIS OF(3-FLUOROPHENYL)-{2-[4-(4-METHOXY-1-METHYL-1H-BENZIMIDAZOL-2-YL)-PIPERAZIN-1-YL]-5-OXO-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YL}-AMINETRIFLUOROACETATE Example 108

Starting from (IV-1) (see 1.2) and (V-5) (see 14.7) Example 108 isprepared and purified as the trifluoroacetate analogously to Example 15(see 10.5). Analytical HPLC-MS (method C): RT=1.73 min.

29. SYNTHESIS OF{2-[4-(7-ETHYL-6,7,8,9-TETRAHYDRO-5H-PYRAZINO[2,3-D]AZEPIN-2-YL)-PIPERAZIN-1-YL]-5-OXO-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YL}-(3-FLUOROPHENYL)-AMINETRIFLUOROACETATE Example 109

Starting from (IV-1) (see 1.2) and (V-6) (see 15.2) Example 109 isprepared and purified as the trifluoroacetate analogously to Example 15(see 10.5). Analytical HPLC-MS (method C): RT=1.6 min.

30. SYNTHESIS OF(3-FLUOROPHENYL)-[5-OXO-2-(4-PYRIMIDIN-4-YL-PIPERAZIN-1-YL)-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YL]-AMINETRIFLUOROACETATE Example 113

Starting from (IV-1) (see 1.2) and 4-piperazin-1-yl-pyrimidin (J. Org.Chem. 1953, 1484) Example 113 is prepared and purified astrifluoroacetate analogously to Example 15 (see 10.5). AnalyticalHPLC-MS (method C): RT=1.56 min.

31. SYNTHESIS OF4-{4-[4-(3-FLUOROPHENYLAMINO)-5-OXO-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-2-YL]-PIPERAZIN-1-YL}-PYRIDIN-2-OLExample 1141

Starting from (IV-1) (see 1.2) and (V-7) (see 17.3) Example 114 isprepared and purified analogously to Example 15 (see 10.5). AnalyticalHPLC-MS (method C): RT=1.61 min.

32. SYNTHESIS OF(3-FLUOROPHENYL)-[5-OXO-2-(4-PYRIDIN-4-YL-PIPERAZIN-1-YL)-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YL]-AMINEExample 117

Starting from (IV-1) (see 1.2) and 1-pyridin-4-yl-piperazine Example 117is prepared and purified analogously to Example 15 (see 10.5).Analytical HPLC-MS (method C): RT=1.56 min.

33. SYNTHESIS OF(3-FLUOROPHENYL)-(2-{4-[4-(4-FLUOROPHENYL)-THIAZOL-2-YL]PIPERAZIN-1-YL}-5-OXO-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YL)-AMINEExample 142

Starting from (IV-1) (see 1.2) and1-[4-(4-fluorophenyl)-thiazol-2-yl]-piperazine Example 142 is preparedand purified analogously to Example 15 (see 10.5).

Analytical HPLC-MS (method C): RT=2.42 min.

34. SYNTHESIS OF[2-(4-BENZO[d]ISOXAZOL-3-YL-PIPERAZIN-1-YL)-5-OXO-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YL]-(3-FLUOROPHENYL)-AMINEExample 144

Starting from (IV-1) (see 1.2) and 3-piperazin-1-yl-benzo[d]isoxazoleExample 144 is prepared and purified analogously to Example 15 (see10.5). Analytical HPLC-MS (method C): RT=2.19 min.

35. SYNTHESIS OF(R)-2-(2-{4-[4-(4-FLUOROPHENYL)-THIAZOL-2-YL]-PIPERAZIN-1-YL}-5-OXO-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YLAMINO)-3-METHYLBUTAN-1-OLExample 148

Starting from (IV-2) (see 2.2) and1-[4-(4-fluorophenyl)-thiazol-2-yl]-piperazine Example 148 is preparedand purified analogously to Example 15 (see 10.5).

Analytical HPLC-MS (method C): RT=1.91 min.

36. SYNTHESIS OF(R)-2-[2-(4-BENZO[d]ISOXAZOL-3-YL-PIPERAZIN-1-YL)-5-OXO-6,7-DIHYDRO-5H-5λ⁴-THIENO[3,2-D]PYRIMIDIN-4-YLAMINO]-3-METHYLBUTAN-1-OLExample 150

Starting from (IV-2) (see 2.2) and 3-piperazin-1-yl-benzo[d]isoxazolExample 150 is prepared and purified analogously to Example 15 (see10.5). Analytical HPLC-MS (method C): RT=1.76 min.

CHROMATOGRAPHICAL METHODS

The Example compounds prepared by the synthesis schemes shownhereinbefore were characterised by the following chromatographicalmethods, which, if carried out, are shown specifically in Table A.

Analytical HPLC-MS, Method A

Waters ZMD Mass spectrometer (positive ionisation (ESI+)), Alliance2690/2695 HPLC (diode array detector, wavelength range: 210 to 500 nm),Waters 2700 Autosampler, Waters 996/2996.

A: water with 0.10% TFAB: acetonitrile with 0.10% TFA

time in min % A % B flow rate in ml/min 0.00 95 5 2.50 0.20 95 5 2.501.50 2 98 2.50 1.70 2 98 2.50 1.90 95 5 2.50 2.20 95 5 2.50

The stationary phase used is a Merck Chromolith™ Flash RP-18e column,4.6 mm×25 mm (column temperature: constant at 25° C.).

Analytical HPLC-MS, Method B

Waters ZMD Mass spectrometer (positive ionisation (ESI+)), Alliance2690/2695 HPLC (diode array detector, wavelength range: 210 to 500 nm),Waters 2700 Autosampler, Waters 996/2996.

A: water with 0.10% NH₃B: acetonitrile with 0.10% NH₃

time in min % A % B flow rate in ml/min 0.00 95 5 3.00 0.20 95 5 3.001.50 2 98 3.00 1.90 2 98 3.00 2.00 2 98 3.00

The stationary phase used is Waters, X-Bridge, C18, 3.5 nm, 4.6×20 mm.Ambient temperature

Analytical HPLC-MS, Method C

Waters ZQ2000 mass spectrometer (positive ionisation (ESI+)), HP1100HPLC (DAD, wavelength range: 210 to 500 nm), and Gilson 215 Autosampler.

A: water with 0.10% TFAB: acetonitrile with 0.10% TFA

time in min % A % B flow rate in ml/min 0.00 95 5 1.50 2.00 0 100 1.502.50 0 100 1.50 2.60 95 5 1.50

The stationary phase used is a Sunfire C18 column, 4.6×50 mm, 3.5 μm,column temperature 40° C.

Analytical HPLC, Method A

Agilent 1100, diode array detection takes place in the wavelength range210-380 nm.

A: water with 0.10% TFAB: acetonitrile with 0.13% TFA

time in min % A % B flow rate in ml/min 0.00 95 5 1.50 0.60 95 5 1.503.40 2 98 1.50 3.90 2 98 1.50 4.20 95 5 1.50 4.90 95 5 1.50

The stationary phase used is a Varian Microsorb column, RP C18, 3 μm,100 A, ambient temperature.

Preparative HPLC-MS, Method A

Waters ZQ2000 mass spectrometer (positive ionisation (ESI+)), HP1100HPLC (DAD, wavelength range: 210-500 nm), and Gilson 215 Autosampler.

A: water with 0.10% TFAB: acetonitrile

time in min % A % B flow rate in ml/min 0.00 90 10 50 1.50 90 10 50 8.0040 60 50 10.00 40 60 50 11.00 90 10 50

The stationary phase used is a Sunfire C18 column, 30×100 mm, 5 μm,ambient temperature.

Preparative HPLC, Method A

Gilson HPLC with Gilson UV-VIS-155 detector, Sampling injector 231 XL.

The wavelength given is the substance-specific UV maximum.

A: water with 0.1% ammonia 35%B: acetonitrile

time in min % A % B flow rate in ml/min  0.00 95 5 180  1.40 95 5 18017.00 2 98 180 18.50 2 98 180 18.70 95 5 180  20.-50 95 5 180

The stationary phase used is a Pursuit XRS RP 18 column, 10 μm, 50×150mm, ambient temperature.

Preparative HPLC, Method B

Gilson HPLC with Gilson UV-VIS-155 detector, Sampling injector 231 XL.

The wavelength given is the substance-specific UV maximum.

A: water with 0.13% TFAB: acetonitrile with 0.1% TFA

time in min % A % B flow rate in ml/min 0.00 95 5 165 1.30 95 5 165 8.902 98 165 10.00 2 98 165 10.50 95 5 165 11.60 95 5 165

The stationary phase used is a Microsorb 18 column, 8 μm, 50×65 mm,ambient temperature

EXAMPLES

The following Examples were prepared analogously to the methods ofsynthesis described hereinbefore (as indicated in the Table). Thesecompounds are suitable for use as PDE4-inhibitors and have IC₅₀ valuesof less than or equal to 1 μmol. The inhibitions (in %) at 1 μM of theindividual Example substances are given in the following Tables ofExamples and were determined as follows:

The Scintillation Proximity Assay (SPA) (GE Healthcare, No. TRKQ7090)was carried out by using the different affinities of cyclic3″-5″-adenosinemonophosphate (cAMP, low affinity) and linear5′-adenosinemonophosphate (AMP, high affinity) for yttrium silicatescintillator beads. The cAMP specific phosphodiesterase (PDE) PDE4Bcleaves the 3′-phosphoester bond of tritium-labelled [H3]-cAMP to form[H3]-5′-AMP. This [H3]-AMP accumulates on the scintillator beads becauseof its higher affinity for them and causes scintillation events (flashesof light) which are measured in a Wallac Microbeta ScintillationCounter.

The experiment starts with a one-hour incubation of [H3]-cAMP with thePDE4B enzyme in assay buffer at 30° C., in each case once with theExample substance to be tested (in a concentration of 1 μM) and oncewithout the Example substance to be tested.

After this incubation, the reaction is stopped by the addition of thebeads. The beads have an opportunity to settle in the next 45 minutes,then the measurement is carried out in the Scintillation Counter. If thesubstance is capable of inhibiting the enzymatic activity of the PDE4B,less [H3]-AMP is produced during the incubation phase and fewerscintillation events can be measured. These results are expressed as thepercentage inhibition at a concentration of the test substance of 1 μM.

The Examples relate to compounds of the following formula 1,

having the characteristics indicated in the following Table A:

TABLE A Chemical structures and details on the preparation of theexample substances 1-156 literature for Prepared preparing theanalogously non-commercial non-commercial Analytical to arylpiperazinearylpiperazine HPLC-MS, RT % Inhibition # R¹ R² R³ Example-#* component(V) component (V) [min], method PDE4B @ 1 μM 1 H

see experim. Section 1.07 method A 94 2 H

see experim. Section 0.87 method A 90 3 H

see experim. Section 1.23 method A 95 4 H

 5 0.85 method A 93 5 H

see experim. Section 1.04 method A 96 6 H

see experim. Section 0.98 method A 93 7 H

see experim. Section 1.12 method A 95 8 H

 5 0.95 method A 94 9 H

 1 1.03 method A 94 10 H

see experim. Section 1.06 method A 94 11 H

71 1.04 method A 96 12 H

13 1.05 method A 95 13 H

see experim. Section 1.09 method B 95 14 H

see experim. Section 1.14 method B 95 15 H

see experim. Section 1.61 method C 97 16 H

see experim. Section 1.86 method C 95 17 H

see experim. Section 1.66 method C 97 18 H

see experim. Section 1.54 method C 96 19 H

23 1.34 method C 69 20 H

23 1.77 method C 97 21 H

23 1.87 method C 96 22 H

23 1.57 method C 97 23 H

see experim. Section 1.5 method C 83 24 H

see experim. Section 1.38 method C 94 25 H

23

U.S. Pat. No. 4,590,273 1.61 method C 97 26 H

23 1.48 method C 95 27 H

23 1.4 method C 94 28 H

see experim. Section 1.31 method C 94 29 H

see experim. Section 1.37 method C 94 30 H

23 1.63 method C 95 31 H

23 1.34 method C 96 32 H

see experim. Section 77 33 H

23 1.48 method C 95 34 H

23 1.49 method C 92 35 H

23 1.48 method C 97 36 H

see experim. Section 1.37 method C 94 37 H

see experim. Section 1.55 method C 90 38 H

see experim. Section 1.45 method C 96 39 H

see experim. Section 0.56 method C 92 40 H

55 1.3 method C 96 41 H

55 1.72 method C 97 42 H

55 1.85 method C 97 43 H

55 1.55 method C 97 44 H

55

see experim. Section § 14.7, component (V-5) 1.48 method C 91 45 H

55

see experim. Section § 26.5, component (V-8) 1.47 method C 95 46 H

55

see experim. Section § 15.2, component (V-6) 1.35 method C 96 47 H

55 1.45 method C 97 48 H

55

see experim. Section § 10.4, component (V-1) 1.34 method C 96 49 H

55

see experim. Section § 11.2, component (V-2) 1.5 method C 94 50 H

55

see experim. Section § 12.1, component (V-3) 1.4 method C 97 51 H

55

see experim. Section § 13.1, component (V-4) 0.55 method C 95 52 H

55

U.S. Pat. No. 4,590,273 1.56 method C 97 53 H

55 1.45 method C 96 54 H

55 1.37 method C 96 55 H

see experim. Section 1.29 method C 95 56 H

55

see experim. Section § 17.3, component (V-7) 1.33 method C 95 57 H

55 1.57 method C 97 58 H

see experim. Section 1.29 method C 91 59 H

55 1.43 method C 96 60 H

55 1.43 method C 95 61 H

71 1.3 method C 97 62 H

71 1.68 method C 97 63 H

71 1.82 method C 97 64 H

71 1.53 method C 98 65 H

71

see experim. Section § 14.7, component (V-5) 1.46 method C 96 66 H

71

see experim. Section § 26.5, component (V-8) 1.46 method C 96 67 H

71

see experim. Section § 15.2, component (V-6) 1.35 method C 97 68 H

71

U.S. Pat. No. 4,590,273 1.53 method C 98 69 H

71 1.44 method C 97 70 H

71 1.36 method C 97 71 H

see experim. Section

J. Org. Chem. 1953, 1484 1.28 method C 96 72 H

71

see experim. Section § 17.3, component (V-7) 1.31 method C 97 73 H

71 1.53 method C 97 74 H

71 1.3 method C 97 75 H

71 1.41 method C 96 76 H

71 1.4 method C 97 77 H

71 1.44 method C 97 78 H

71

see experim. Section § 10.4, component (V-1) 1.33 method C 97 79 H

71

see experim. Section § 11.2, component (V-2) 1.47 method C 96 80 H

71

see experim. Section § 12.1, component (V-3) 1.4 method C 97 81 H

71

see experim. Section § 13.1, component (V-4) 1.25 method C 97 82 H

87 1.33 method C 96 83 H

87 1.77 method C 97 84 H

87 1.89 method C 97 85 H

87 1.56 method C 97 86 H

87

see experim. Section § 14.7, component (V-5) 1.5 method C 92 87 H

see experim. Section 1.48 method C 96 88 H

87

see experim. Section § 15.2, component (V-6) 1.38 method C 96 89 H

87

U.S. Pat. No. 4,590,273 1.59 method C 97 90 H

87 1.47 method C 96 91 H

87 1.4 method C 96 92 H

87

J. Org. Chem. 1953, 1484 1.3 method C 96 93 H

87

see experim. Section § 17.3, component (V-7) 1.36 method C 95 94 H

87 1.62 method C 97 95 H

87 1.33 method C 96 96 H

see experim. Section 1.32 method C 93 97 H

87 1.46 method C 96 98 H

87 1.47 method C 96 99 H

87 1.46 method C 97 100 H

87

see experim. Section § 10.4, component (V-1) 1.37 method C 96 101 H

87

see experim. Section § 11.2, component (V-2) 1.53 method C 95 102 H

87

see experim. Section § 12.1, component (V-3) 1.43 method C 96 103 H

87

see experim. Section § 13.1, component (V-4) 1.28 method C 96 104 H

108  1.57 method C 97 105 H

108  2.2 method C 96 106 H

108  2.4 method C 96 107 H

108  1.8 method C 96 108 H

see experim. Section 1.73 method C 95 109 H

see experim. Section 1.6 method C 96 110 H

108 

U.S. Pat. No. 4,590,273 1.91 method C 97 111 H

108  1.72 method C 96 112 H

108  1.65 method C 97 113 H

see experim. Section 1.56 method C 96 114 H

see experim. Section 1.61 method C 96 115 H

108  1.89 method C 96 116 H

108  1.58 method C 97 117 H

see experim. Section 1.56 method C 96 118 H

108  1.81 method C 97 119 H

108  1.8 method C 96 120 H

108  1.71 method C 97 121 H

55 1.38 method C 95 122 H

55 1.89 method C 97 123 H

55 1.6 method C 95 124 H

55 1.72 method C 96 125 H

55 1.43 method C 94 126 H

55 1.67 method C 95 127 H

55 1.8 method C 94 128 H

55 1.73 method C 94 129 H

55 1.75 method C 96 130 H

55 1.73 method C 95 131 H

87 1.4 method C 95 132 H

87 1.8 method C 96 133 H

87 1.64 method C 96 134 H

87 1.75 method C 96 135 H

87 1.46 method C 94 136 H

87 1.72 method C 96 137 H

87 1.84 method C 94 138 H

87 1.77 method C 95 139 H

87 1.65 method C 97 140 H

87 1.77 method C 97 141 H

108  1.65 method C 96 142 H

see experim. Section 1.42 method C 95 143 H

108  2.04 method C 96 144 H

see experim. Section 2.19 method C 96 145 H

108  1.7 method C 95 146 H

108  2.12 method C 95 147 H

23 1.41 method C 94 148 H

see experim. Section 1.91 method C 95 149 H

23 1.63 method C 95 150 H

see experim. Section 1.76 method C 95 151 H

23 1.45 method C 92 152 H

23 1.73 method C 94 153 H

23 1.84 method C 91 154 H

23 1.76 method C 94 155 H

23 1.74 method C 95 156 H

23 1.77 method C 95 *the Example may be prepared and purifiedanalogously.

Indications

As has been found, the compounds of formula 1 are characterised by theirwide range of applications in the therapeutic field. Particular mentionshould be made of those applications for which the compounds accordingto the invention of formula 1 are preferably suited on account of theirpharmaceutical efficacy as PDE4 inhibitors. Examples include respiratoryor gastrointestinal diseases or complaints, inflammatory diseases of thejoints, skin or eyes, cancers, and also diseases of the peripheral orcentral nervous system.

Particular mention should be made of the prevention and treatment ofdiseases of the airways and of the lung which are accompanied byincreased mucus production, inflammations and/or obstructive diseases ofthe airways. Examples include acute, allergic or chronic bronchitis,chronic obstructive bronchitis (COPD), coughing, pulmonary emphysema,allergic or non-allergic rhinitis or sinusitis, chronic rhinitis orsinusitis, asthma, alveolitis, Farmer's disease, hyperreactive airways,infectious bronchitis or pneumonitis, paediatric asthma, bronchiectases,pulmonary fibrosis, ARDS (acute adult respiratory distress syndrome),bronchial oedema, pulmonary oedema, bronchitis, pneumonia orinterstitial pneumonia triggered by various causes, such as aspiration,inhalation of toxic gases, or bronchitis, pneumonia or interstitialpneumonia as a result of heart failure, irradiation, chemotherapy,cystic fibrosis or mucoviscidosis, or alpha1-antitrypsin deficiency.

Also deserving special mention is the treatment of inflammatory diseasesof the gastrointestinal tract. Examples include acute or chronicinflammatory changes in gall bladder inflammation, Crohn's disease,ulcerative colitis, inflammatory pseudopolyps, juvenile polyps, colitiscystica profunda, pneumatosis cystoides intestinales, diseases of thebile duct and gall bladder, e.g. gallstones and conglomerates, for thetreatment of inflammatory diseases of the joints such as rheumatoidarthritis or inflammatory diseases of the skin and eyes.

Preferential mention should also be made of the treatment of cancers.Examples include all forms of acute and chronic leukaemias such as acutelymphatic and acute myeloid leukaemia, chronic lymphatic and chronicmyeloid leukaemia as well as bone tumours such as e.g. osteosarcoma andall kinds of gliomas such as e.g. oligodendroglioma and glioblastoma.

Preferential mention should also be made of the prevention and treatmentof diseases of the peripheral or central nervous system. Examples ofthese include depression, bipolar or manic depression, acute and chronicanxiety states, schizophrenia, Alzheimer's disease, Parkinson's disease,acute and chronic multiple sclerosis or acute and chronic pain as wellas injuries to the brain caused by stroke, hypoxia or craniocerebraltrauma.

Particularly preferably the present invention relates to the use ofcompounds of formula 1 for preparing a pharmaceutical composition forthe treatment of inflammatory or obstructive diseases of the upper andlower respiratory tract including the lungs, such as for exampleallergic rhinitis, chronic rhinitis, bronchiectasis, cystic fibrosis,idiopathic pulmonary fibrosis, fibrosing alveolitis, COPD, chronicbronchitis, chronic sinusitis, asthma, Crohn's disease, ulcerativecolitis, particularly COPD, chronic bronchitis and asthma.

It is most preferable to use the compounds of formula 1 for thetreatment of inflammatory and obstructive diseases such as COPD, chronicbronchitis, chronic sinusitis, asthma, Crohn's disease, ulcerativecolitis, particularly COPD, chronic bronchitis and asthma.

It is also preferable to use the compounds of formula 1 for thetreatment of diseases of the peripheral or central nervous system suchas depression, bipolar or manic depression, acute and chronic anxietystates, schizophrenia, Alzheimer's disease, Parkinson's disease, acuteand chronic multiple sclerosis or acute and chronic pain as well asinjuries to the brain caused by stroke, hypoxia or craniocerebraltrauma.

An outstanding aspect of the present invention is the reduced profile ofside effects. This means, within the scope of the invention, being ableto administer a dose of a pharmaceutical composition without inducingvomiting, preferably nausea and most preferably malaise in the patient.It is particularly preferable to be able to administer a therapeuticallyeffective quantity of substance without inducing emesis or nausea, atevery stage of the disease.

Combinations

The compounds of formula 1 may be used on their own or in conjunctionwith other active substances of formula 1 according to the invention. Ifdesired the compounds of formula 1 may also be used in combination withother pharmacologically active substances. It is preferable to use forthis purpose active substances selected for example from amongbetamimetics, anticholinergics, corticosteroids, other PDE4-inhibitors,LTD4-antagonists, EGFR-inhibitors, MRP4-inhibitors, dopamine agonists,H1-antihistamines, PAF-antagonists and PI3-kinase inhibitors or doubleor triple combinations thereof, such as for example combinations ofcompounds of formula 1 with one or two compounds selected from among

-   betamimetics, corticosteroids, PDE4-inhibitors, EGFR-inhibitors and    LTD4-antagonists,-   anticholinergics, betamimetics, corticosteroids, PDE4-inhibitors,    EGFR-inhibitors and LTD4-antagonists,-   PDE4-inhibitors, corticosteroids, EGFR-inhibitors and    LTD4-antagonists-   EGFR-inhibitors, PDE4-inhibitors and LTD4-antagonists-   EGFR-inhibitors and LTD4-antagonists-   CCR3-inhibitors, iNOS-inhibitors (inducible nitric oxide    synthase-inhibitors), (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin    (hereinafter referred to as “BH4”) and the derivatives thereof as    mentioned in WO 2006/120176 and SYK-inhibitors (spleen tyrosine    kinase inhibitors)-   anticholinergics, betamimetics, corticosteroids, PDE4-inhibitors and    MRP4-inhibitors.

The invention also relates to combinations of three active substances,each chosen from one of the above-mentioned categories of compounds.

Suitable betamimetics used are preferably compounds selected from amongalbuterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol,fenoterol, formoterol, arformoterol, zinterol, hexoprenaline, ibuterol,isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine,metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol,rimiterol, ritodrine, salmeterol, salmefamol, soterenol, sulphonterol,tiaramide, terbutaline, tolubuterol, CHF-1035, HOKU-81, KUL-1248,3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzyl-sulphonamide,5-[2-(5.6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one,4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone,1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1.4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one,1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol,6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(ethyl4-phenoxy-acetate)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-aceticacid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3.4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyricacid,8-{2-[2-(3.4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneand1-(4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol,optionally in the form of the racemates, enantiomers, diastereomers andoptionally in the form of the pharmacologically acceptable acid additionsalts, solvates or hydrates thereof.

Preferably the betamimetics are selected from among bambuterol,bitolterol, carbuterol, clenbuterol, fenoterol, formoterol,hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, salmeterol,sulphonterol, terbutaline, tolubuterol,3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulphonamide,5-[2-(5.6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one,4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone,1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,143-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one,1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol,6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(ethyl-4-phenoxy-acetate)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-aceticacid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1.1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyricacid,8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneand1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol,optionally in the form of the racemates, enantiomers, diastereomers andoptionally in the form of the pharmacologically acceptable acid additionsalts, solvates or hydrates thereof.

Particularly preferred betamimetics are selected from among fenoterol,formoterol, salmeterol,3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulphonamide,5-[2-(5.6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinoline-2-one,1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(ethyl4-phenoxy-acetate)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-aceticacid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyricacid,8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneand1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,optionally in the form of the racemates, enantiomers, diastereomers andoptionally in the form of the pharmacologically acceptable acid additionsalts, solvates or hydrates thereof.

Of these betamimetics the particularly preferred ones according to theinvention are formoterol, salmeterol,3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulphonamide,6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(ethyl4-phenoxy-acetate)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-aceticacid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1.1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyricacid,8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneand5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinoline-2-one,optionally in the form of the racemates, enantiomers, diastereomers andoptionally in the form of the pharmacologically acceptable acid additionsalts, solvates or hydrates thereof.

According to the invention the acid addition salts of the betamimeticsare preferably selected from among the hydrochloride, hydrobromide,hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate,hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulphonate, preferably the hydrochloride, hydrobromide,hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.Of the above-mentioned acid addition salts the salts of hydrochloricacid, methanesulphonic acid, benzoic acid and acetic acid areparticularly preferred according to the invention.

The anticholinergics used are preferably compounds selected from amongthe tiotropium salts, oxitropium salts, flutropium salts, ipratropiumsalts, glycopyrronium salts, trospium salts, tropenol2,2-diphenylpropionate methobromide, scopine 2,2-diphenylpropionatemethobromide, scopine 2-fluoro-2,2-diphenylacetate methobromide,tropenol 2-fluoro-2,2-diphenylacetate methobromide, tropenol3,3′,4,4′-tetrafluorobenzilate methobromide, scopine3,3′,4,4′-tetrafluorobenzilate methobromide, tropenol4,4′-difluorobenzilate methobromide, scopine 4,4′-difluorobenzilatemethobromide, tropenol 3,3′-difluorobenzilate methobromide, -scopine3,3′-difluorobenzilate methobromide, tropenol9-hydroxy-fluorene-9-carboxylate -methobromide, tropenol9-fluoro-fluorene-9-carboxylate -methobromide, scopine9-hydroxy-fluoren-9-carboxylate methobromide, scopine9-fluoro-fluorene-9-carboxylate methobromide, tropenol9-methyl-fluorene-9-carboxylate methobromide, scopine9-methyl-fluorene-9-carboxylate methobromide, cyclopropyltropinebenzilate methobromide, cyclopropyltropine 2,2-diphenylpropionatemethobromide, -cyclopropyltropine 9-hydroxy-xanthene-9-carboxylatemethobromide, cyclopropyltropine 9-methyl-fluorene-9-carboxylatemethobromide, cyclopropyltropine 9-methyl-xanthene-9-carboxylatemethobromide, cyclopropyltropine 9-hydroxy-fluorene-9-carboxylatemethobromide, methyl cyclopropyltropine 4,4′-difluorobenzilatemethobromide, tropenol 9-hydroxy-xanthene-9-carboxylate -methobromide,-scopine 9-hydroxy-xanthene-9-carboxylate methobromide, tropenol9-methyl-xanthene-9-carboxylate methobromide, scopine9-methyl-xanthene-9-carboxylate methobromide, tropenol9-ethyl-xanthene-9-carboxylate methobromide, tropenol9-difluoromethyl-xanthene-9-carboxylate methobromide, scopine9-hydroxymethyl-xanthene-9-carboxylate methobromide, optionally in theform of the solvates or hydrates thereof.

In the above-mentioned salts the cations tiotropium, oxitropium,flutropium, ipratropium, glycopyrronium and trospium are thepharmacologically active ingredients. As anions, the above-mentionedsalts may preferably contain chloride, bromide, iodide, sulphate,phosphate, methanesulphonate, nitrate, maleate, acetate, citrate,fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate,while chloride, bromide, iodide, sulphate, methanesulphonate orp-toluenesulphonate are preferred as counter-ions. Of all the salts, thechlorides, bromides, iodides and methanesulphonate are particularlypreferred.

Of particular importance is tiotropium bromide. In the case oftiotropium bromide the pharmaceutical combinations according to theinvention preferably contain it in the form of the crystallinetiotropium bromide monohydrate, which is known from WO 02/30928. If thetiotropium bromide is used in anhydrous form in the pharmaceuticalcombinations according to the invention, it is preferable to useanhydrous crystalline tiotropium bromide, which is known from WO03/000265.

Corticosteroids used here are preferably compounds selected from amongprednisolone, prednisone, butixocortpropionate, flunisolide,beclomethasone, triamcinolone, budesonide, fluticasone, mometasone,ciclesonide, rofleponide, dexamethasone, betamethasone, deflazacort,RPR-106541, NS-126, (S)-fluoromethyl6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionateand (S)-(2-oxo-tetrahydro-furan-3S-yl)6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionate,optionally in the form of the racemates, enantiomers or diastereomersthereof and optionally in the form of the salts and derivatives,solvates and/or hydrates thereof.

Particularly preferred is the steroid selected from among flunisolide,beclomethasone, triamcinolone, budesonide, fluticasone, mometasone,ciclesonide, rofleponide, dexamethasone, NS-126, (S)-fluoromethyl6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionateand (S)-(2-oxo-tetrahydro-furan-3S-yl)6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionate,optionally in the form of the racemates, enantiomers or diastereomersthereof and optionally in the form of the salts and derivatives,solvates and/or hydrates thereof.

Particularly preferred is the steroid selected from among budesonide,fluticasone, mometasone, ciclesonide and (S)-fluoromethyl6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate,optionally in the form of the racemates, enantiomers or diastereomersthereof and optionally in the form of the salts and derivatives,solvates and/or hydrates thereof.

Any reference to steroids includes a reference to any salts orderivatives, hydrates or solvates thereof which may exist. Examples ofpossible salts and derivatives of the steroids may be: alkali metalsalts, such as for example sodium or potassium salts, sulfobenzoates,phosphates, isonicotinates, acetates, propionates, dihydrogenphosphates, palmitates, pivalates or furoates thereof.

Other PDE4 inhibitors which may be used are preferably compoundsselected from among enprofyllin, theophyllin, roflumilast, ariflo(cilomilast), tofimilast, pumafentrin, lirimilast, arofyllin, atizoram,D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418,PD-168787, T-440, T-2585, V-11294A, CI-1018, CDC-801, CDC-3052, D-22888,YM-58997, Z-15370,N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide,(−)p-[(4aR*.10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1.6]naphthyridin-6-yl]-N,N-diisopropylbenzamide,(R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone,3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N-2-cyano-5-methyl-isothioureido]benzyl)-2-pyrrolidone,cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid],2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-one,cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-14],(R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate,(S)-(−)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate,9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridineand9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine,optionally in the form of the racemates, enantiomers or diastereomersand optionally in the form of the pharmacologically acceptable acidaddition salts, solvates and/or hydrates thereof.

Particularly preferably the PDE4-inhibitor is selected from amongenprofyllin, roflumilast, ariflo (cilomilast), arofyllin, atizoram,AWD-12-281 (GW-842470), T-440, T-2585, PD-168787, V-11294A, CI-1018,CDC-801, D-22888, YM-58997, Z-15370,N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxy-benzamide,cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid],2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one,cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-01],9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridineand9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine,optionally in the form of the racemates, enantiomers or diastereomersand optionally in the form of the pharmacologically acceptable acidaddition salts, solvates and/or hydrates thereof.

Particularly preferably the PDE4-inhibitor is selected from amongroflumilast, ariflo (cilomilast), arofyllin, AWD-12-281 (GW-842470),2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one,cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-14],atizoram,Z-15370,9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridineand9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine,optionally in the form of the racemates, enantiomers or diastereomersand optionally in the form of the pharmacologically acceptable acidaddition salts, solvates and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which theabove-mentioned PDE4-inhibitors might be in a position to form aremeant, for example, salts selected from among the hydrochloride,hydrobromide, hydroiodide, hydrosulphate, hydrophosphate,hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferablyhydrochloride, hydrobromide, hydrosulphate, hydrophosphate,hydrofumarate and hydromethanesulphonate.

LTD4-antagonists which may be used are preferably compounds selectedfrom among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523),MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321,1-(((R)-(3-(2-(6,7-difluoro-2-quinolinypethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-aceticacid,1-(((1(R)-3(3-(2-(2.3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclo-propane-aceticacid and[2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]aceticacid, optionally in the form of the racemates, enantiomers ordiastereomers, optionally in the form of the pharmacologicallyacceptable acid addition salts and optionally in the form of the saltsand derivatives, solvates and/or hydrates thereof.

Preferably the LTD4-antagonist is selected from among montelukast,pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507),VUF-5078, VUF-K-8707 and L-733321, optionally in the form of theracemates, enantiomers or diastereomers, optionally in the form of thepharmacologically acceptable acid addition salts and optionally in theform of the salts and derivatives, solvates and/or hydrates thereof.

Particularly preferably the LTD4-antagonist is selected from amongmontelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001 andMEN-91507 (LM-1507), optionally in the form of the racemates,enantiomers or diastereomers, optionally in the form of thepharmacologically acceptable acid addition salts and optionally in theform of the salts and derivatives, solvates and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which theLTD4-antagonists may be capable of forming are meant, for example, saltsselected from among the hydrochloride, hydrobromide, hydroiodide,hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate,hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide,hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.By salts or derivatives which the LTD4-antagonists may be capable offorming are meant, for example: alkali metal salts, such as, forexample, sodium or potassium salts, alkaline earth metal salts,sulphobenzoates, phosphates, isonicotinates, acetates, propionates,dihydrogen phosphates, palmitates, pivalates or furoates.

The EGFR-inhibitors used are preferably compounds selected from among4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({-4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({-4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({-4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({-4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine,3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline,4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethansulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline,cetuximab, trastuzumab, ABX-EGF and Mab ICR-62, optionally in the formof the racemates, enantiomers or diastereomers thereof, optionally inthe form of the pharmacologically acceptable acid addition saltsthereof, the solvates and/or hydrates thereof.

Preferred EGFR-inhibitors are selected from among4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({-4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({-4-(N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({-4-(N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({-4-(N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({-4-(N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine,3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline,4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethansulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline,and cetuximab, optionally in the form of the racemates, enantiomers ordiastereomers thereof, optionally in the form of the pharmacologicallyacceptable acid addition salts thereof, the solvates and/or hydratesthereof.

It is particularly preferable within the scope of the present inventionto use those EGFR-inhibitors which are selected from among4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({-4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine,3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethansulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline,and4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,optionally in the form of the racemates, enantiomers or diastereomersthereof, optionally in the form of the pharmacologically acceptable acidaddition salts thereof, the solvates and/or hydrates thereof.

Particularly preferred EGFR-inhibitors according to the invention arethe compounds selected from among4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({-4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazolineand4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline,optionally in the form of the racemates, enantiomers or diastereomersthereof, optionally in the form of the pharmacologically acceptable acidaddition salts thereof, the solvates and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which theEGFR-inhibitors may be capable of forming are meant, for example, saltsselected from among the hydrochloride, hydrobromide, hydroiodide,hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate,hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide,hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.

Examples of dopamine agonists which may be used preferably includecompounds selected from among bromocriptine, cabergoline,alpha-dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol,ropinirol, talipexol, terguride and viozan. Any reference to theabove-mentioned dopamine agonists within the scope of the presentinvention includes a reference to any pharmacologically acceptable acidaddition salts and optionally hydrates thereof which may exist. By thephysiologically acceptable acid addition salts which may be formed bythe above-mentioned dopamine agonists are meant, for example,pharmaceutically acceptable salts which are selected from the salts ofhydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lacticacid, citric acid, tartaric acid and maleic acid.

Examples of H1-antihistamines preferably include compounds selected fromamong epinastine, cetirizine, azelastine, fexofenadine, levocabastine,loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine,bamipin, cexchlorpheniramine, pheniramine, doxylamine,chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine,ebastine, desloratidine and meclozine. Any reference to theabove-mentioned H1-antihistamines within the scope of the presentinvention includes a reference to any pharmacologically acceptable acidaddition salts which may exist.

Examples of PAF-antagonists preferably include compounds selected fromamong4-(2-chlorophenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanon-1-yl]-6H-thieno-[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepines,6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclo-penta-[4,5]thieno-[3,24][1,2,4]triazolo[4,3-a][1,4]diazepines.

MRP4-inhibitors used are preferably compounds selected from amongN-acetyl-dinitrophenyl-cysteine, cGMP, cholate, diclofenac,dehydroepiandrosterone 3-glucuronide, dehydroepiandrosterone 3-sulphate,dilazep, dinitrophenyl-s-glutathione, estradiol 17-beta-glucuronide,estradiol 3,17-disulphate, estradiol 3-glucuronide, estradiol3-sulphate, estrone 3-sulphate, flurbiprofen, folate,N5-formyl-tetrahydrofolate, glycocholate, clycolithocholic acidsulphate, ibuprofen, indomethacin, indoprofen, ketoprofen, lithocholicacid sulphate, methotrexate, MK571((E)-3-[[[342-(7-chloro-2-quinolinyl)ethenyl]phenyl]-[[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoicacid), alpha-naphthyl-beta-D-glucuronide, nitrobenzyl mercaptopurineriboside, probenecid, PSC833, sildenafil, sulfinpyrazone,taurochenodeoxycholate, taurocholate, taurodeoxycholate,taurolithocholate, taurolithocholic acid sulphate, topotecan, trequinsinand zaprinast, dipyridamole, optionally in the form of the racemates,enantiomers, diastereomers and the pharmacologically acceptable acidaddition salts and hydrates thereof.

Preferably the invention relates to the use of MRP4-inhibitors forpreparing a pharmaceutical composition for the treatment of respiratorycomplaints, containing the PDE4B-inhibitors and MRP4-inhibitors, theMRP4-inhibitors preferably being selected from amongN-acetyl-dinitrophenyl-cysteine, dehydroepiandrosterone 3-sulphate,dilazep, dinitrophenyl-5-glutathione, estradiol 3,17-disulphate,flurbiprofen, glycocholate, glycolithocholic acid sulphate, ibuprofen,indomethacin, indoprofen, lithocholic acid sulphate, MK571, PSC833,sildenafil, taurochenodeoxycholate, taurocholate, taurolithocholate,taurolithocholic acid sulphate, trequinsin and zaprinast, dipyridamole,optionally in the form of the racemates, enantiomers, diastereomers andthe pharmacologically acceptable acid addition salts and hydratesthereof.

The invention relates more preferably to the use of MRP4-inhibitors forpreparing a pharmaceutical composition for treating respiratorycomplaints, containing the PDE4B-inhibitors and MRP4-inhibitorsaccording to the invention, the MRP4-inhibitors preferably beingselected from among dehydroepiandrosterone 3-sulphate, estradiol3,17-disulphate, flurbiprofen, indomethacin, indoprofen, MK571,taurocholate, optionally in the form of the racemates, enantiomers,diastereomers and the pharmacologically acceptable acid addition saltsand hydrates thereof. The separation of enantiomers from the racematescan be carried out using methods known from the art (e.g. chromatographyon chiral phases, etc.).

By acid addition salts with pharmacologically acceptable acids aremeant, for example, salts selected from among the hydrochlorides,hydrobromides, hydroiodides, hydrosulphates, hydrophosphates,hydromethanesulphonates, hydronitrates, hydromaleates, hydroacetates,hydrobenzoates, hydrocitrates, hydrofumarates, hydrotartrates,hydrooxalates, hydrosuccinates, hydrobenzoates andhydro-p-toluenesulphonates, preferably the hydrochlorides,hydrobromides, hydrosulphates, hydrophosphates, hydrofumarates andhydromethanesulphonates.

The invention further relates to pharmaceutical preparations whichcontain a triple combination of the PDE4B-inhibitors, MRP4-inhibitorsand another active substance according to the invention, such as, forexample, an anticholinergic, a steroid, an LTD4-antagonist or abetamimetic, and the preparation thereof and the use thereof fortreating respiratory complaints.

Compounds which may be used as iNOS inhibitors are compounds selectedfrom among: S-(2-aminoethyl)isothiourea, aminoguanidine,2-aminomethylpyridine, AMT, L-canavanine, 2-iminopiperidine,S-isopropylisothiourea, S-methylisothiourea, S-ethylisothiourea,S-methyltiocitrullin, S-ethylthiocitrulline, L-NA(N^(ω)-nitro-L-arginine), L-NAME (N^(ω)-nitro-L-argininemethylester),L-NMMA (N^(G)-monomethyl-L-arginine), L-NIO(N^(ω)-iminoethyl-L-ornithine), L-NIL (N^(ω)-iminoethyl-lysine),(S)-6-acetimidoylamino-2-amino-hexanoic acid (1H-tetrazol-5-yl)-amide(SC-51) (J. Med. Chem. 2002, 45, 1686-1689), 1400W,(S)-4-(2-acetimidoylamino-ethylsulphanyl)-2-amino-butyric acid(GW274150) (Bioorg. Med. Chem. Lett. 2000, 10, 597-600),242-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine(BYK191023) (Mol. Pharmacol. 2006, 69, 328-337),2-((R)-3-amino-1-phenyl-propoxy)-4-chloro-5-fluorobenzonitrile (WO01/62704),2-((1R,3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-6-trifluoromethyl-nicotinonitrile(WO 2004/041794),2-((1R,3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-4-chloro-benzonitrile(WO 2004/041794),2-((1R,3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-5-chloro-benzonitrile(WO 2004/041794),(2S,4R)-2-amino-4-(2-chloro-5-trifluoromethyl-phenylsulphanyl)-4-thiazol-5-yl-butan-1-01(WO 2004/041794),2-((1R,3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-5-chloro-nicotinonitrile(WO 2004/041794),4-((S)-3-amino-4-hydroxy-1-phenyl-butylsulphanyl)-6-methoxy-nicotinonitrile(WO 02/090332), substituted 3-phenyl-3,4-dihydro-1-isoquinolinamine suchas e.g. AR-C102222 (J. Med. Chem. 2003, 46, 913-916),(1S,5S,6R)-7-chloro-5-methyl-2-aza-bicyclo[4.1.0]hept-2-en-3-ylamine(ONO-1714) (Biochem. Biophys. Res. Commun. 2000, 270, 663-667),(4R,5R)-5-ethyl-4-methyl-thiazolidin-2-ylideneamine (Bioorg. Med. Chem.2004, 12, 4101), (4R,5R)-5-ethyl-4-methyl-selenazolidin-2-ylideneamine(Bioorg. Med. Chem. Lett. 2005, 15, 1361), 4-aminotetrahydrobiopterine(Curr. Drug Metabol. 2002, 3, 119-121),(E)-3-(4-chloro-phenyl)-N-(1-{2-oxo-2-[4-(6-trifluoromethyl-pyrimidin-4-yloxy)-piperidin-1-yl]-ethylcarbamoyl}-2-pyridin-2-yl-ethyl)-acrylamide(FR260330) (Eur. J. Pharmacol. 2005, 509, 71-76),3-(2,4-difluoro-phenyl)-6-[2-(4-imidazol-1-ylmethyl-phenoxy)-ethoxy]-2-phenyl-pyridine(PPA250) (J. Pharmacol. Exp. Ther. 2002, 303, 52-57), methyl3-{[(benzo[1,3]dioxol-5-ylmethyl)-carbamoyl]-methyl}-4-(2-imidazol-1-yl-pyrimidin-4-yl)-piperazine-1-carboxylate(BBS-1) (Drugs Future 2004, 29, 45-52),(R)-1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidine-2-carboxylicacid (2-benzo[1,3]dioxol-5-yl-ethyl)amide (BBS-2) (Drugs Future 2004,29, 45-52) and the pharmaceutical salts, prodrugs or solvates thereof.

Examples of iNOS-inhibitors within the scope of the present inventionmay also include antisense oligonucleotides, particularly thoseantisense oligonucleotides which bind iNOS-coding nucleic acids. Forexample, WO 01/52902 describes antisense oligonucleotides, particularlyantisense oligonucleotides, which bind iNOS coding nucleic acids, formodulating the expression of iNOS. iNOS-antisense oligonucleotides asdescribed particularly in WO 01/52902 may therefore also be combinedwith the PDE4-inhibitors of the present invention on account of theirsimilar effect to the iNOS-inhibitors.

Compounds which may be used as SYK-inhibitors are preferably compoundsselected from among:

-   2-[(2-aminoethyl)amino]-4-[(3-bromophenyl)amino]-5-pyrimidinecarboxamide;-   2-[[7-(3,4-dimethoxyphenyl)imidazo[1,2-c]pyrimidin-5-yl]amino]-3-pyridinecarboxamide;-   6-[[5-fluoro-2-[3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-dimethyl-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one;-   N-[3-bromo-7-(4-methoxyphenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine    7-(4-methoxyphenyl)-N-methyl-1,6-naphthyridin-5-amine;-   N-[7-(4-methoxyphenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(2-thienyl)-1,6-naphthyridin-5-yl-1,3-propanediamine;-   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,2-ethanediamine;-   N-[7-(4-methoxyphenyl)-2-(trifluoromethyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(4-methoxyphenyl)-3-phenyl-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-(7-phenyl-1,6-naphthyridin-5-yl)-1,3-propanediamine;-   N-[7-(3-fluorophenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(3-chlorophenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[3-(trifluoromethoxy)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(4-fluorophenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(4-fluorophenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(4-chlorophenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(4′-methyl[1,1′-biphenyl]-4-yl)-1,6-naphthyridin-1,3-propanediamine;-   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[4-(diethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[4-(4-morpholinyl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(4-bromophenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(4-methylphenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[4-(methylthio)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[4-(1-methylethyl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   7-[4-(dimethylamino)phenyl]-N-methyl-1,6-naphthyridin-5-amine;-   7-[4-(dimethylamino)phenyl]-N,N-dimethyl-1,6-naphthyridin-5-amine;-   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,4-butanediamine;-   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,5-pentanediamine;-   3-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]oxy]-1-propanol;-   4-[5-(4-aminobutoxy)-1,6-naphthyridin-7-yl]-N,N-dimethyl-benzenamine;-   4-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]amino]-1-butanol;-   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-N-methyl-1,3-propanediamine;-   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-N′-methyl-1,3-propanediamine;-   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-N,N′-dimethyl-1,3-propanediamine;-   1-amino-3-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]amino]-2-propanol;-   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-2,2-dimethyl-1,3-propanediamine;-   7-[4-(dimethylamino)phenyl]-N-(3-pyridinylmethyl)-1,6-naphthyridin-5-amine;-   N-[(2-aminophenyl)methyl]-7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-amine;-   N-[7-[6-(dimethylamino)[1,1′-biphenyl]-3-yl]-1,6-naphthyridin-5-yl]-1,3-propanediamine,    ;-   N-[7-[3-chloro-4-(diethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[4-(dimethylamino)-3-methoxyphenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[4-(diethylamino)phenyl]-3-methyl-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(3′-fluoro[1,1′-biphenyl]-3-yl)-1,6-naphthyridin-5-yl]-1,2-ethanediamine,-   N-[7-(4-methoxyphenyl)-1,6-naphthyridin-5-yl]-1,6-naphthyridine-1,3-propanediamine;-   N,N′-bis(3-aminopropyl)-7-(4-methoxyphenyl)-2,5-diamine;-   N-[7-(4-methoxyphenyl)-2-(phenylmethoxy)-1,6-naphthyridin-5-yl]-1,6-naphthyridine-1,3-propanediamine;

N5-(3-aminopropyl)-7-(4-methoxyphenyl)-N2-(phenylmethyl)-2,5-diamine;

-   N-[7-(2-naphthalenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(2′-fluoro[1,1′-biphenyl]-4-yl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(3,4,5-trimethoxyphenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(3,4-dimethylphenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   1-amino-3-[[7-(2-naphthalenyl)-1,6-naphthyridin-5-yl]amino]-2-propanol;-   1-amino-3-[[7-(2′-fluoro[1,1′-biphenyl]-4-yl)-1,6-naphthyridin-5-yl]amino]-2-propanol;-   1-amino-3-[[7-(4′-methoxy[1,1′-biphenyl]-4-yl)-1,6-naphthyridin-5-yl]amino]-2-propanol;-   1-amino-3-[[7-(3,4,5-trimethoxyphenyl)-1,6-naphthyridin-5-yl]amino]-2-propanol;-   1-amino-3-[[7-(4-bromophenyl)-1,6-naphthyridin-5-yl]amino]-2-propanol;-   N-[7-(4′-methoxy[1,1′-biphenyl]-4-yl)-1,6-naphthyridin-5-yl]-2,2-dimethyl-1,3-propanediamine;-   1-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]amino]-2-propanol;-   2-[[2-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]amino]ethyl]thio]-ethanol;-   7-[4-(dimethylamino)phenyl]-N-(3-methyl-5-isoxazolyl)-1,6-naphthyridin-5-amine;-   7-[4-(dimethylamino)phenyl]-N-4-pyrimidinyl-1,6-naphthyridin-5-amine;-   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,3-cyclohexanediamine;-   N,N-dimethyl-4-[5-(1-piperazinyl)-1,6-naphthyridin-7-yl]-benzenamine;-   4-[5-(2-methoxyethoxy)-1,6-naphthyridin-7-yl]-N,N-dimethyl-benzenamine;-   1-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-4-piperidinol;-   1-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-3-pyrrolidinol;-   7-[4-(dimethylamino)phenyl]-N-(2-furanylmethyl)-1,6-naphthyridin-5-amine;-   7-[4-(dimethylamino)phenyl]-N-[3-(1H-imidazol-1-yl)propyl]-1,6-naphthyridin-5-amine;-   1-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-4-piperidinecarboxamide;-   1-[3-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]amino]propyl]-2-pyrrolidinone;-   N-[3′-[5-[(3-aminopropyl)amino]-1,6-naphthyridin-7-yl][1,1′-biphenyl]-3-yl]-acetamide;-   N-[7-(4′-fluoro[1,1′-biphenyl]-4-yl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[4′-[5-[(3-aminopropyl)amino]-1,6-naphthyridin-7-yl][1,1′-biphenyl]-3-yl]-acetamide;-   N-[7-[4-(1,3-benzodioxol-5-yl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[4-(2-thienyl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[4-fluoro-3-(trifluoromethyl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[4-(3-pyridinyl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(1,3-benzodioxol-5-yl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(6-methoxy-2-naphthalenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   7-[4-(dimethylamino)phenyl]-N-(4-pyridinylmethyl)-1,6-naphthyridin-5-amine;-   3-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]methylamino]-propanenitrile;-   7-[4-(dimethylamino)phenyl]-N-[1-(phenylmethyl)-4-piperidinyl]-1,6-naphthyridin-5-amine;-   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,2-cyclohexanediamine,    (1R,2S)-rel-.-   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,2-benzenedimethanamine;-   N-[7-[4-(diethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,4-butanediamine;-   N-[7-[3′.5′-bis(trifluoromethyl)[1,1′-biphenyl]-4-yl]-1,6-naphthyridin-5-yl].3-propanediamine;-   N-[7-(3′-methoxy[1,1′-biphenyl]-4-yl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(3′-fluoro[1,1′-biphenyl]-4-yl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   4-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]oxy]-1-butanol;-   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,4-cyclohexanediamine;-   7-[4-(dimethylamino)phenyl]-N-(2.2.6.6-tetramethyl-4-piperidinyl)-1,6-naphthyridin-5-amine;-   N-[7-[3-bromo-4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(1-methyl-1H-indol-5-yl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[3-(trifluoromethyl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[4-(trifluoromethyl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(3-bromo-4-methoxyphenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[4-[[3-(dimethylamino)propyl]methylamino]phenyl]-1,6-naphthyridin-5-yl]-1,4-cyclohexanediamine;-   N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1,6-naphthyridin-5-yl]-1,4-cyclohexanediamine;-   N-[7-[4-(dimethylamino)-3-methoxyphenyl]-1,6-naphthyridin-5-yl]-1,4-cyclohexanediamine;-   N-[7-[4-(4-morpholinyl)phenyl]-1,6-naphthyridin-5-yl]-1,4-cyclohexanediamine;-   N-[7-[3-bromo-4-(4-morpholinyl)phenyl]-1,6-naphthyridin-5-yl]-1,4-cyclohexanediamine;-   4-[[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1,6-naphthyridin-5-yl]oxy]-cyclohexanol;-   N-[7-[3-bromo-4-(4-morpholinyl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N,N-dimethyl-4-[5-(4-methyl-1-piperazinyl)-1,6-naphthyridin-7-yl]-benzenamine;-   4-[[7-[4-[[3-(dimethylamino)propyl]methylamino]phenyl]-1,6-naphthyridin-5-yl]oxy]-cyclohexanol;-   N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1,6-naphthyridin-5-yl]-1,4-butanediamine;-   1,1-dimethylethyl[3-[[5-[(3-aminopropyl)amino]-7-(4-methoxyphenyl)-1,6-naphthyridin-2-yl]amino]propyl]-carbamate.

Formulations

Suitable forms for administration are for example tablets, capsules,solutions, syrups, emulsions or inhalable powders or aerosols. Thecontent of the pharmaceutically effective compound(s) in each caseshould be in the range from 0.1 to 90 wt. %, preferably 0.5 to 50 wt. %of the total composition, i.e. in amounts which are sufficient toachieve the dosage range specified hereinafter.

The preparations may be administered orally in the form of a tablet, asa powder, as a powder in a capsule (e.g. a hard gelatine capsule), as asolution or suspension. When administered by inhalation the activesubstance combination may be given as a powder, as an aqueous oraqueous-ethanolic solution or using a propellant gas formulation.

Preferably, therefore, pharmaceutical formulations are characterised bythe content of one or more compounds of formula 1 according to thepreferred embodiments above.

It is particularly preferable if the compounds of formula 1 areadministered orally, and it is also particularly preferable if they areadministered once or twice a day. Suitable tablets may be obtained, forexample, by mixing the active substance(s) with known excipients, forexample inert diluents such as calcium carbonate, calcium phosphate orlactose, disintegrants such as corn starch or alginic acid, binders suchas starch or gelatine, lubricants such as magnesium stearate or talcand/or agents for delaying release, such as carboxymethyl cellulose,cellulose acetate phthalate, or polyvinyl acetate. The tablets may alsocomprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups containing the active substances or combinations thereofaccording to the invention may additionally contain a sweetener such assaccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. aflavouring such as vanillin or orange extract. They may also containsuspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules. Suitable suppositories may be made forexample by mixing with carriers provided for this purpose, such asneutral fats or polyethyleneglycol or the derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silicic acid andsilicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers(e.g. lignin, spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

For oral administration the tablets may, of course, contain, apart fromthe abovementioned carriers, additives such as sodium citrate, calciumcarbonate and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatine and the like. Moreover,lubricants such as magnesium stearate, sodium lauryl sulphate and talcmay be used at the same time for the tabletting process. In the case ofaqueous suspensions the active substances may be combined with variousflavour enhancers or colourings in addition to the excipients mentionedabove.

It is also preferred if the compounds of formula 1 are administered byinhalation, particularly preferably if they are administered once ortwice a day. For this purpose, the compounds of formula 1 have to bemade available in forms suitable for inhalation. Inhalable preparationsinclude inhalable powders, propellant-containing metered-dose aerosolsor propellant-free inhalable solutions, which are optionally present inadmixture with conventional physiologically acceptable excipients.

Within the scope of the present invention, the term propellant-freeinhalable solutions also includes concentrates or sterile ready-to-useinhalable solutions. The preparations which may be used according to theinvention are described in more detail in the next part of thespecification.

Inhalable Powders

If the active substances of formula 1 are present in admixture withphysiologically acceptable excipients, the following physiologicallyacceptable excipients may be used to prepare the inhalable powdersaccording to the invention: monosaccharides (e.g. glucose or arabinose),disaccharides (e.g. lactose, saccharose, maltose), oligo- andpolysaccharides (e.g. dextran), polyalcohols (e.g. sorbitol, mannitol,xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures ofthese excipients with one another. Preferably, mono- or disaccharidesare used, while the use of lactose or glucose is preferred,particularly, but not exclusively, in the form of their hydrates. Forthe purposes of the invention, lactose is the particularly preferredexcipient, while lactose monohydrate is most particularly preferred.Methods of preparing the inhalable powders according to the invention bygrinding and micronising and by finally mixing the components togetherare known from the prior art.

Propellant-Containing Inhalable Aerosols

The propellant-containing inhalable aerosols which may be used accordingto the invention may contain the compounds of formula 1 dissolved in thepropellant gas or in dispersed form. The propellant gases which may beused to prepare the inhalation aerosols according to the invention areknown from the prior art. Suitable propellant gases are selected fromamong hydrocarbons such as n-propane, n-butane or isobutane andhalohydrocarbons such as preferably fluorinated derivatives of methane,ethane, propane, butane, cyclopropane or cyclobutane. The propellantgases mentioned above may be used on their own or in mixtures thereof.Particularly preferred propellant gases are fluorinated alkanederivatives selected from TG134a (1,1,1,2-tetrafluoroethane), TG227(1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof. Thepropellant-driven inhalation aerosols used within the scope of the useaccording to the invention may also contain other ingredients such asco-solvents, stabilisers, surfactants, antioxidants, lubricants and pHadjusters. All these ingredients are known in the art.

Propellant-Free Inhalable Solutions

The compounds of formula 1 according to the invention are preferablyused to prepare propellant-free inhalable solutions and inhalablesuspensions. Solvents used for this purpose include aqueous oralcoholic, preferably ethanolic solutions. The solvent may be water onits own or a mixture of water and ethanol. The solutions or suspensionsare adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids.The pH may be adjusted using acids selected from inorganic or organicacids. Examples of particularly suitable inorganic acids includehydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/orphosphoric acid. Examples of particularly suitable organic acids includeascorbic acid, citric acid, malic acid, tartaric acid, maleic acid,succinic acid, fumaric acid, acetic acid, formic acid and/or propionicacid etc. Preferred inorganic acids are hydrochloric and sulphuricacids. It is also possible to use the acids which have already formed anacid addition salt with one of the active substances. Of the organicacids, ascorbic acid, fumaric acid and citric acid are preferred. Ifdesired, mixtures of the above acids may also be used, particularly inthe case of acids which have other properties in addition to theiracidifying qualities, e.g. as flavourings, antioxidants or complexingagents, such as citric acid or ascorbic acid, for example. According tothe invention, it is particularly preferred to use hydrochloric acid toadjust the pH.

Co-solvents and/or other excipients may be added to the propellant-freeinhalable solutions used for the purpose according to the invention.Preferred co-solvents are those which contain hydroxyl groups or otherpolar groups, e.g. alcohols—particularly isopropyl alcohol,glycols—particularly propyleneglycol, polyethyleneglycol,polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols andpolyoxyethylene fatty acid esters. The terms excipients and additives inthis context denote any pharmacologically acceptable substance which isnot an active substance but which can be formulated with the activesubstance or substances in the pharmacologically suitable solvent inorder to improve the qualitative properties of the active substanceformulation. Preferably, these substances have no pharmacological effector, in connection with the desired therapy, no appreciable or at leastno undesirable pharmacological effect. The excipients and additivesinclude, for example, surfactants such as soya lecithin, oleic acid,sorbitan esters, such as polysorbates, polyvinylpyrrolidone, otherstabilisers, complexing agents, antioxidants and/or preservatives whichguarantee or prolong the shelf life of the finished pharmaceuticalformulation, flavourings, vitamins and/or other additives known in theart. The additives also include pharmacologically acceptable salts suchas sodium chloride as isotonic agents. The preferred excipients includeantioxidants such as ascorbic acid, for example, provided that it hasnot already been used to adjust the pH, vitamin A, vitamin E,tocopherols and similar vitamins or provitamins occurring in the humanbody. Preservatives may be used to protect the formulation fromcontamination with pathogens. Suitable preservatives are those which areknown in the art, particularly cetyl pyridinium chloride, benzalkoniumchloride or benzoic acid or benzoates such as sodium benzoate in theconcentration known from the prior art.

For the treatment forms described above, ready-to-use packs of amedicament for the treatment of respiratory complaints are provided,containing an enclosed description including for example the wordsrespiratory disease, COPD or asthma, together withdihydrothienopyrimidine and one or more combination partners selectedfrom those described above.

1. Compounds of formula 1

wherein X denotes SO or SO₂, R¹ denotes H, C₁₋₆-alkyl, R² is H or agroup selected from among C₁₋₁₀-alkyl and C₂₋₆-alkenyl, which mayoptionally be substituted by der optionally by one or more groupsselected from halogen and C₁₋₃-fluoroalkyl or which may optionally besubstituted by one or more groups selected from among OR^(2.1),COOR^(2.1), CONR^(2.2)R^(2.3), SR^(2.1), SO—R^(2.1), SO₂—R^(2.1),C₆₋₁₀-aryl, a het, a hetaryl, a mono- or bicyclic C₃₋₁₀-cycloalkyl,CH₂—NR^(2.2)R^(2.3) and NR^(2.2)R^(2.3), which may in turn optionally besubstituted by one or more groups selected from among OH, halogen,OR^(2.1), oxo, CF₃, CHF₂, CH₂F, C₁₋₆-alkyl, C₁₋₆-alkanol, C₆₋₁₀-aryl,COOR^(2.1), CH₂—NR^(2.2)R^(2.3) and NR^(2.2)R^(2.3), wherein R^(2.1) isH or a group selected from among C₁₋₆-alkyl, C₁₋₆-alkanol,C₁₋₃-haloalkyl, mono- or bicyclic C₃₋₁₀-cycloalkyl,C₆₋₁₀-aryl-C₁₋₆-alkylene, mono- or bicyclic hetaryl-C₁₋₆-alkylene,het-C₁₋₆-alkylene, C₃₋₁₀-cycloalkyl-C₁₋₆-alkylene, a mono- or bicyclicC₆₋₁₀-aryl, a hetaryl and a het, which may optionally be substituted byone or more groups selected from among OH, O—(C₁₋₃-alkyl), halogen,C₁₋₆-alkyl and C₆₋₁₀-aryl, while R^(2.2) and R^(2.3) independently ofone another denote H or a group selected from among C₁₋₆-alkyl, mono- orbicyclic C₃₋₁₀ cycloalkyl, aryl-C₁₋₆-alkylene, hetaryl-C₁₋₆-alkylene,mono- or bicyclic C₆₋₁₀-aryl, het, hetaryl, CO—NH₂, CO—NHCH₃,CO—N(CH₃)₂, SO₂—(C₁-C₂-alkyl), CO—R^(2.1) and COOR^(2.1), which mayoptionally be substituted by one or more groups selected from among OH,halogen, C₁₋₆-alkyl, C₆₋₁₀-aryl and COOR^(2.1), while het is a three- toeleven-membered, mono- or bicyclic, saturated or partially saturated,optionally anellated or optionally bridged heterocycle, which contains1, 2, 3 or 4 heteroatoms selected independently of one another fromamong N, S or O, and while hetaryl is a five- to eleven-membered, mono-or bicyclic, optionally anellated heteroaryl which contains 1, 2, 3 or 4heteroatoms selected independently of one another from among N, S or O,and while cycloalkyl may be saturated or partially saturated, or R²denotes a mono- or polycyclic C₃₋₁₀ cycloalkyl, which may optionally bebridged one or more times by C₁₋₃-alkyl groups and which may optionallybe substituted by a group selected from among branched or unbranchedC₁₋₆-alkanol, C₁₋₃-fluoroalkyl, C₁₋₃-alkylene-OR^(2.1), COOR^(2.1),SO₂—NR^(2.2)—R^(2.3), het, C₆₋₁₀-aryl, C₆₋₁₀-aryl-C₁₋₆-alkylene,hetaryl-C₁₋₆-alkylene, mono- or bicyclic C₃₋₁₀ cycloalkyl andNR^(2.2)R^(2.3), which may optionally be substituted by one or moregroups selected from among OH, OR^(2.1), oxo, halogen, CF₃, CHF₂, CH₂F,C₆₋₁₀-aryl and NR^(2.2)R^(2.3), or R² denotes a mono- or polycyclicC₆₋₁₀-aryl, which may optionally be substituted by OH, SH or halogen orby one or more groups selected from among OR^(2.1), COOR^(2.1),NR^(2.2)—R^(2.3), CH₂—NR^(2.2)R^(2.3), C₃₋₁₀-cycloalkyl, het,—C₁₋₆-alkyl, C₁₋₃-fluoroalkyl, C₆₋₁₀-aryl-C₁₋₆-alkylene,het-C₁₋₆-alkylene, hetaryl-C₁₋₆-alkylene, C₆₋₁₀-aryl, SO₂—CH₃,SO₂—CH₂CH₃ and SO₂—NR^(2.2)R^(2.3), which may in turn optionally besubstituted by one or more groups selected from among OH, OR^(2.1), CF₃,CHF₂, CH₂F, oxo, halogen, CF₃, CHF₂, CH₂F, C₁₋₆-alkyl, C₆₋₁₀-aryl andNR^(2.2)R^(2.3), or R² denotes a group selected from among het andhetaryl, which may optionally be substituted by one or more groupsselected from among halogen, OH, oxo, CF₃, CHF₂ and CH₂F or by one ormore groups selected from among OR^(2.1), C₁₋₃-alkylene-OR^(2.1),SR^(2.1), SO—R^(2.1) and SO₂—R^(2.1), COOR^(2.1), COR^(2.1),C₁₋₆-alkanol, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, C₆₋₁₀-aryl-C₁₋₆-alkylene,hetaryl-C₁₋₆-alkylene, het, hetaryl, C₁₋₃-alkylene-OR^(2.1) andNR^(2.2)R^(2.3), which may in turn optionally be substituted by one ormore groups selected from among OH, OR^(2.1), oxo, halogen, CF₃, CHF₂,CH₂F, C₆₋₁₀-aryl and NR^(2.2)R^(2.3), or wherein NR¹R² together denotesa heterocyclic four- to seven-membered ring which may optionally bebridged, which contains 1, 2 or 3 heteroatoms selected from among N, Oand S and which may optionally be substituted by one or more groupsselected from among OH, OR^(2.1), C₁₋₃-alkylene-O^(R.1), oxo, halogen,C₁₋₆-alkyl, C₆₋₁₀-aryl, COOR^(2.1), CH₂—NR^(2.2)—COO—R^(2.1),CH₂—NR^(2.2)—CO—R^(2.1), CH₂—NR^(2.2)—CO—CH₂—NR^(2.2)R^(2.3),CH₂—NR^(2.2)—SO₂—C₁₋₃-alkyl, CH₂—NR^(2.2)—SO₂—NR^(2.2)R^(2.3),CH₂—NR^(2.2)—CO—NR^(2.2)R^(2.3), CO—NR^(2.2)R^(2.3), CH₂—NR^(2.2)R^(2.3)and NR^(2.2)R^(2.3), and wherein R³ is a group selected from among a hetand a hetaryl, which may optionally be substituted by one or more groupsselected from among halogen, C₁₋₃-fluoroalkyl, CN, OH, oxo, —O—R^(2.1),—COOR^(2.1), SO—R^(2.1), SO₂—R^(2.1), C₆₋₁₀-aryl,C₁₋₃-alkylene-C₆₋₁₀-aryl, —C₁₋₃-alkylene-NR^(2.2)R^(2.3),—NR^(2.2)R^(2.3), a C₃₋₁₀-cycloalkyl, a C₁₋₃-alkylene-C₃₋₁₀-cycloalkyl,a het, a hetaryl, C₁₋₃-alkylene-hetaryl, and C₁₋₃-alkylene-het, whichmay in turn optionally be substituted by one or more groups selectedfrom among OH, halogen, —C₁₋₃-fluoroalkyl, C₆₋₁₀-aryl, —COO(C₁₋₃-alkyl)and O—(C₁₋₃-alkyl), and pharmacologically acceptable salts thereof. 2.Compounds of formula 1 according to claim 1, wherein X denotes SO orSO₂, R¹ denotes H R² is H or C₁₋₁₀-alkyl, which may optionally besubstituted by one or more groups selected from halogen andC₁₋₃-fluoroalkyl or which may optionally be substituted by one or moregroups selected from among OR^(2.1), COOR^(2.1), CONR^(2.2)R^(2.3),SR^(2.1), SO—R^(2.1), SO₂—R^(2.1), phenyl, a monocyclic three- toseven-membered heterocycle, a monocyclic five- to six-memberedheteroaryl, a monocyclic C₃₋₇-cycloalkyl, CH₂—NR^(2.2)R^(2.3) andNR^(2.2)R^(2.3), which may in turn optionally be substituted by one ormore groups selected from among OH, halogen, OR^(2.1), oxo, CF₃, CHF₂,CH₂F, C₁₋₆-alkanol, phenyl, COOR², CH₂—NR^(2.2)R^(2.3) andNR^(2.2)R^(2.3), while R^(2.1) is H or a group selected from amongC₁₋₆-alkyl, C₁₋₆-alkanol, C₁₋₃-haloalkyl, monocyclic C₃₋₇ cycloalkyl,phenyl-C₁₋₆-alkylene, hetaryl-C₁₋₆-alkylene, het-C₁₋₆-alkylene,C₃₋₇-cycloalkyl-C₁₋₆-alkylene, phenyl, a hetaryl and a het, which mayoptionally be substituted by one or more groups selected from among OH,halogen, C₁₋₆-alkyl, O—(C₁₋₃-alkyl) and phenyl, while R^(2.2) andR^(2.3) independently of one another denote H or a group selected fromamong C₁₋₆-alkyl, monocyclic C₃₋₇ cycloalkyl, phenyl-C₁₋₃-alkylene,hetaryl-C₁₋₃-alkylene, phenyl, het, hetaryl, CO—NH₂, CO—NHCH₃,CON(CH₃)₂, —SO₂—(C₁₋₂-alkyl), —CO—R^(2.1) and —COOR^(2.1), which mayoptionally be substituted by one or more groups selected from among OH,halogen, C₁₋₆-alkyl, phenyl and COOR^(2.1), while het is a three- toseven-membered, monocyclic, saturated or partially saturated heterocycleor a seven- to eleven-membered, bicyclic, saturated or partiallysaturated heterocycle, which contains 1, 2, 3 or 4 heteroatoms selectedindependently of one another from among N, S or O, and wherein hetarylis a five- to six-membered, monocyclic, aromatic heteroaryl or a seven-to eleven-membered, bicyclic, aromatic heteroaryl which contains in eachcase 1, 2, 3 or 4 heteroatoms selected independently of one another fromamong N, S or O, and wherein cycloalkyl may be saturated or partiallysaturated, or R² denotes a monocyclic C₃₋₇ cycloalkyl, which mayoptionally be substituted by a group selected from among branched orunbranched C₁₋₆-alkanol, C₁₋₃-fluoroalkyl, OR^(2.1),C₁₋₃-alkylene-OR^(2.1), COOR^(2.1), SO₂—NR^(2.2)R^(2.3), het, phenyl,—C₁₋₆-alkyl, phenyl-C₁₋₆-alkylene, hetaryl-C₁₋₆-alkylene, monocyclicC₃₋₇-cycloalkyl and NR^(2.2)R^(2.3), which may optionally be substitutedby one or more groups selected from among OH, OR^(2.1), oxo, halogen,CF₃, CHF₂, CH₂F, C₁₋₆-alkyl, phenyl and NR^(2.2)R^(2.3), or R² denotes aphenyl which may optionally be substituted by OH, SH or halogen or byone or more groups selected from among OR^(2.1), COOR^(2.1),NR^(2.2)R^(2.3), CH₂—NR^(2.2)R^(2.3), C₃₋₇-cycloalkyl, het, C₁₋₆-alkyl,C₁₋₃-fluoroalkyl, phenyl-C₁₋₆-alkylene, het-C₁₋₆-alkylene,hetaryl-C₁₋₆-alkylene, phenyl, SO₂—CH₃, SO₂—CH₂CH₃ andSO₂—NR^(2.2)R^(2.3), which may in turn optionally be substituted by oneor more groups selected from among OH, OR^(2.1), oxo, halogen, CF₃,CHF₂, CH₂F, C₁₋₆-alkyl, phenyl and NR^(2.2)R^(2.3), or R² denotes agroup selected from among a het and a hetaryl, which may optionally besubstituted by one or more groups selected from among halogen, OH, oxo,CF₃, CHF₂ and CH₂F or by one or more groups selected from amongOR^(2.1), —C₁₋₃-alkylene-OR^(2.1), SR^(2.1), SO—R^(2.1), SO₂—R^(2.1),COOR^(2.1), COR^(2.1), C₁₋₆-alkanol, C₃₋₁₀-cycloalkyl, phenyl,C₁₋₆-alkyl, phenyl-C₁₋₆-alkylene, hetaryl-C₁₋₆-alkylene, het, hetaryl,C₁₋₆-alkanol and NR^(2.2)R^(2.3), which may in turn optionally besubstituted by one or more groups selected from among OH, OR^(2.1), oxo,halogen, CF₃, CHF₂, CH₂F, C₁₋₆-alkyl, phenyl and NR^(2.2)R^(2.3), andwherein R³ is a group selected from among a het and a hetaryl, which mayoptionally be substituted by one or more groups selected from amonghalogen, C₁₋₃-fluoroalkyl, CN, OH, oxo, —O—R^(2.1), —COOR^(2.1),SO—R^(2.1), SO₂—R^(2.1), C₆₋₁₀-aryl, C₁₋₃-alkylene-C₆₋₁₀-aryl,—C₁₋₃-alkylene-NR^(2.2)R^(2.3), —NR^(2.2)R^(2.3), a C₃₋₁₀-cycloalkyl, aC₁₋₃-alkylene-C₃₋₁₀-cycloalkyl, a het, a hetaryl, C₁₋₃-alkylene-hetaryl,and C₁₋₃-alkylene-het, which may in turn optionally be substituted byone or more groups selected from among OH, halogen, —C₁₋₃-fluoroalkyl,C₆₋₁₀-aryl, —COO(C₁₋₃-alkyl) and O—(C₁₋₃-alkyl), as well aspharmacologically acceptable salts thereof.
 3. Compounds of formula 1according to claim 1, wherein X denotes SO, R¹ denotes H R² is H orC₁₋₆-alkyl, which may optionally be substituted by one or more groupsselected from F, CF₃, CHF₂ or CH₂F or which may optionally besubstituted by one or more groups selected from among OR^(2.1),COOR^(2.1), CONR^(2.2)R^(2.3), SR^(2.1), SO—R^(2.1), SO₂—R^(2.1),phenyl, a het, a hetaryl, a monocyclic C₃₋₇-cycloalkyl,CH₂—NR^(2.2)R^(2.3) and NR^(2.2)R^(2.3), which may in turn optionally besubstituted by one or more groups selected from among OH, F, Cl, Br,CF₃, CHF₂, CH₂F, OR^(2.1), oxo, methyl, ethyl, propyl, isopropyl,C₁₋₂-alkanol, phenyl, COOR^(2.1), CH₂—NR^(2.2)R^(2.3) andNR^(2.2)R^(2.3), while R^(2.1) is H or a group selected from amongmethyl, ethyl, propyl, isopropyl, monocyclic C₃₋₇ cycloalkyl,phenyl-C₁₋₂-alkylene, hetaryl-C₁₋₂-alkylene, het-C₁₋₂-alkylene,C₃₋₇-cycloalkyl-C₁₋₂-alkylene, phenyl, a hetaryl and a het, which mayoptionally be substituted by one or more groups selected from among OH,halogen, methyl, ethyl, propyl, isopropyl, O-methyl, O-ethyl, O-propyl,O-isopropyl and phenyl, while R^(2.2) and R^(2.3) independently of oneanother denote H or a group selected from among methyl, ethyl, propyl,isopropyl, monocyclic C₃₋₇-cycloalkyl, phenyl-C₁₋₃-alkylene,hetaryl-C₁₋₃-alkylene, phenyl, het, hetaryl, CO—NH₂, CO—NHCH₃,CON(CH₃)₂, SO₂—(C₁-C₂-alkyl), CO—R^(2.1) and COOR^(2.1), which mayoptionally be substituted by one or more groups selected from among OH,F, Cl, Br, methyl, ethyl, propyl, isopropyl, phenyl and COOR^(2.1),wherein het is a three- to seven-membered, monocyclic, saturated orpartially saturated heterocycle which contains 1, 2 or 3 heteroatomsselected independently of one another from among N, S or O, and whereinhetaryl is a five- to six-membered, monocyclic, aromatic heteroarylwhich contains 1, 2 or 3 heteroatoms selected independently of oneanother from among N, S or O, and wherein cycloalkyl may be saturated orpartially saturated, or R² denotes a monocyclic C₃₋₇ cycloalkyl, whichmay optionally be substituted by a group selected from among branched orunbranched C₁₋₂-alkanol, C₁₋₃-fluoroalkyl, C₁₋₃-alkylene-OR^(2.1),OR^(2.1), COOR^(2.1), SO₂—NR^(2.2)R^(2.3), het, methyl, ethyl, propyl,isopropyl, phenyl, phenyl-C₁₋₂-alkylene, hetaryl-C₁₋₂-alkylene,monocyclic C₃₋₇ cycloalkyl and NR^(2.2)R^(2.3), which may optionally besubstituted by one or more groups selected from among OH, OR^(2.1), oxo,halogen, CF₃, CHF₂, CH₂F, methyl, ethyl, propyl, isopropyl, phenyl andNR^(2.2)R^(2.3), or R² denotes a phenyl which may optionally besubstituted by OH, SH, F, Cl or Br or by one or more groups selectedfrom among OR^(2.1), COOR^(2.1), NR^(2.2)R^(2.3), CH₂—NR^(2.2)R^(2.3),C₃₋₇-cycloalkyl, het, methyl, ethyl, propyl, isopropyl, CF₃, CHF₂, CH₂F,phenyl-C₁₋₂-alkylene, het-C₁₋₂-alkylene, hetaryl-C₁₋₂-alkylene, phenyl,SO₂—CH₃, SO₂—CH₂CH₃ and SO₂—NR^(2.2)R^(2.3), which may in turnoptionally be substituted by one or more groups selected from among OH,OR^(2.1), oxo, F, Cl, Br, CF₃, CHF₂, CH₂F, methyl, ethyl, propyl,isopropyl, phenyl and NR^(2.2)R^(2.3), or R² denotes a group selectedfrom among a het and a hetaryl, which is optionally substituted by oneor more groups selected from among F, Cl, Br, OH, oxo, CF₃, CHF₂, CH₂Fand SH or by one or more groups selected from among OR^(2.1),C₁₋₃-alkylene-OR^(2.1), SR^(2.1), SO—R^(2.1), SO₂—R^(2.1), COOR^(2.1),COR^(2.1), C₁₋₂-alkanol, C₃₋₁₀-cycloalkyl, phenyl, methyl, ethyl,propyl, isopropyl, phenyl-C₁₋₂-alkylene, hetaryl-C₁₋₂-alkylene, het,hetaryl, C₁₋₂-alkanol and NR^(2.2)R^(2.3), which may in turn optionallybe substituted by one or more groups selected from among OH, OR^(2.1),oxo, F, Cl, Br, CF₃, CHF₂, CH₂F, C₁₋₆-alkyl, phenyl and NR^(2.2)R^(2.3),and wherein R³ denotes a group selected from among a saturated orpartially saturated, monocyclic three- to seven-membered heterocycle, asaturated or partially saturated, bicyclic five- to eleven-memberedheterocycle, a monocyclic, five- to six-membered heteroaryl and abicyclic, seven- to eleven-membered heteroaryl, which contains in eachcase 1, 2, 3 or 4 heteroatoms selected independently of one another fromamong N, O and S and which may optionally be substituted in each case byone or more groups selected from among halogen, C₁₋₃-fluoroalkyl, CN,OH, oxo, alkyl, —O—R^(2.1), —COOR^(2.1), SO—R^(2.1), SO₂—R^(2.1),C₆₋₁₀-aryl, C₁₋₃-alkylene-C₆₋₁₀-aryl, —C₁₋₃-alkylene-NR^(2.2)R^(2.3),—NR^(2.2)R^(2.3), a C₃₋₁₀-cycloalkyl, a C₁₋₃-alkylene-C₃₋₁₀-cycloalkyl,het, a hetaryl, C₁₋₃-alkylene-hetaryl, and C₁₋₃-alkylene-het, which mayin turn optionally be substituted by one or more groups selected fromamong OH, halogen, —C₁₋₃-fluoroalkyl, C₆₋₁₀-aryl, —COO(C₁₋₃-alkyl) andO—(C₁₋₃-alkyl), as well as pharmacologically acceptable salts thereof.4. Compounds of formula 1 according to one claim 1, wherein R² denotes agroup according to the formula 2

wherein R⁵ is OH or NH₂ and wherein R⁴ is a group selected from amongC₁₋₄-alkyl, hetaryl and phenyl, which may optionally be substituted byone or more groups selected from among OH, F, Br, OR^(2.1), oxo, methyl,ethyl, C₁₋₂-alkanol, phenyl, COOR^(2.1), CH₂—NR^(2.2)R^(2.3) andNR^(2.2)R^(2.3), as well as pharmacologically acceptable salts thereof.5. Compounds of formula 1 according to claim 4, wherein R² denotes agroup according to the formula 2

wherein R⁵ is OH or NH₂ and wherein R⁴ is methyl, ethyl, propyl,isopropyl, as well as pharmacologically acceptable salts thereof. 6.Compounds of formula 1 according to claim 1, wherein R² is a monocyclicthree-, four-, five-, six- or seven-membered cycloalkyl ring which mayoptionally be substituted in the spiro position by a group selected fromamong —CH₂—OR^(2.1), branched or unbranched C₂₋₆-alkylene-OR^(2.1),methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, —CF₃,CHF₂, CH₂F and C₂₋₄-fluoroalkyl, while R^(2.1) is selected from amongmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, as well aspharmacologically acceptable salts thereof.
 7. Compounds of formula 1according to claim 1, wherein R² is a phenyl which may optionally besubstituted in one or both meta positions by one or more groups selectedfrom among methyl, ethyl, propyl, isopropyl, cyclopropyl, F, Cl, Br, OH,OR^(2.1), COOR^(2.1), CF₃, CHF₂, CH₂F, NH₂ and N(CH₃)₂, wherein R^(2.1)may be H, methyl or ethyl, as well as pharmacologically acceptable saltsthereof.
 8. Compounds of formula 1 according to claim 1, wherein R² is amonocyclic, saturated three-, four-, five-, six or seven-memberedheterocycle with 1, 2 or 3 heteroatoms each selected from among N, O andS, which may optionally be substituted by one or more groups selectedfrom among fluorine, chlorine, bromine, CF₃, CHF₂, CH₂F, OH, oxo and SHor by one or more groups selected from among OR^(2.1),C₁₋₃-alkylene-OR^(2.1), SR^(2.1), SO—R^(2.1), SO₂—R^(2.1), COOR^(2.1),COR^(2.1), C₁₋₆-alkanol, C₃₋₁₀-cycloalkyl, phenyl, C₁₋₆-alkyl,phenyl-C₁₋₆-alkylene, hetaryl-C₁₋₆-alkylene, het, hetaryl andNR^(2.2)R^(2.3), which may in turn optionally be substituted by one ormore groups selected from among OH, OR^(2.1), oxo, F, Cl, CF₃, CHF₂,CH₂F, C₁₋₆-alkyl, phenyl and NR^(2.2)R^(2.3), wherein R^(2.1), R^(2.2)and R^(2.3) are defined as in claim 1, as well as pharmacologicallyacceptable salts thereof.
 9. Compounds of formula 1 according to claim8, wherein R² is a group selected from among a monocyclic, saturated,six-membered heterocycle with a heteroatom selected from among N, O andS, which may optionally be substituted by one or more groups selectedfrom among F, Cl, Br, CF₃, CHF₂, CH₂F, OH, oxo, NH₂, NHCH₃, N(CH₃)₂,methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy and ethoxy, aswell as pharmacologically acceptable salts thereof.
 10. Compounds offormula 1 according to claim 8, wherein R² denotes a group selected fromamong piperidine or tetrahydropyran, which may optionally be substitutedby one or more groups selected from among F, Cl, Br, OH, CF₃, CHF₂,CH₂F, NH₂, NHCH₃, N(CH₃)₂, oxo, methyl and methoxy, as well aspharmacologically acceptable salts thereof.
 11. Compounds of formula 1according to claim 1, wherein R³ is a monocyclic five or six-memberedheteroaryl ring, which may optionally be substituted by one or moregroups selected from among F, Cl, Br, CF₃, CHF₂, CH₂F, CN, OH, -methyl,ethyl, propyl, isopropyl, —O-methyl, O-ethyl, —COOmethyl, —COOethyl,SO₂—(CH₃), SO—(CH₃), SO₂—(CH₂CH₃), SO—(CH₂CH₃), phenyl,-methylene-phenyl, -ethylene-phenyl, —NH₂, —NH(CH₃), N(CH₃)₂,-methylene-NH₂, -methylene-NH(CH₃), -methylene-N(CH₃)₂, aC₃₋₆-cycloalkyl, a methylene-C₃₋₆-cycloalkyl, a saturated or partiallysaturated, five- to six-membered heterocycle, a five- or six-memberedheteroaryl, -methylene-hetaryl, and -methylene-het, which may in turnoptionally be substituted by one or more groups selected from among OH,F, Cl, Br, CF₃, CHF₂, CH₂F, methyl, ethyl, propyl, isopropyl, phenyl,—COO(CH₃), —O-methyl and —O-ethyl, as well as pharmacologicallyacceptable salts thereof.
 12. Compounds of formula 1 according to claim1, wherein R³ is a bicyclic 9- to 11-membered saturated, unsaturated orpartially saturated heterocycle, which may optionally be substituted byone or more groups selected from among F, Cl, Br, CF₃, CHF₂, CH₂F, CN,OH, -methyl, ethyl, propyl, isopropyl, —O-methyl, O-ethyl, —COOmethyl,—COOethyl, SO₂—(CH₃), SO—(CH₃), SO₂—(CH₂CH₃), SO—(CH₂CH₃), phenyl,—methylene-phenyl, -ethylene-phenyl, —NH2, —NH(CH₃), N(CH₃)₂,-methylene-NH₂, -methylene-NH(CH₃), -methylene-N(CH₃)₂, a—C₃₋₆-cycloalkyl, a -methylene-C₃₋₆-cycloalkyl, a saturated, partiallyunsaturated or unsaturated 5- to 6-membered heterocycle, a 5- to6-membered heteroaryl, -methylene-hetaryl, and -methylene-het, which mayin turn optionally be substituted by one or more groups selected fromamong OH, F, Cl, Br, CF₃, CHF₂, CH₂F, methyl, ethyl, propyl, isopropyl,phenyl, —COO(CH₃), —O-methyl and —O-ethyl, as well as pharmacologicallyacceptable salts thereof.
 13. Compounds of formula 1 according to claim11, wherein R³ is a monocyclic five or six-membered heteroaryl ringselected from among pyrrole, pyrazole, furan, thiophene, thiazole,imidazole, oxazole, pyridazine, pyrimidine, pyrazine, thiadiazole,oxadiazole, triazine, isoxazole, isothiazole and pyridine, which mayoptionally be substituted by one or more groups selected from among F,Cl, Br, CF₃, CHF₂, CH₂F, CN, OH, -methyl, ethyl, propyl, isopropyl,—O-methyl, O-ethyl, —COOmethyl, —COOethyl, SO₂—(CH₃), SO₂—(CH₂CH₃),phenyl, -methylene-phenyl, -ethylene-phenyl, —NH₂, —NH(CH₃), N(CH₃)₂,-methylene-NH₂, -methylene-NH(CH₃), -methylene-N(CH₃)₂, aC₃₋₆-cycloalkyl, a methylene-C₃₋₆-cycloalkyl, a het, a hetaryl,-methylene-hetaryl, and -methylene-het, which may in turn optionally besubstituted by one or more groups selected from among OH, F, Cl, Br,CF₃, CHF₂, CH₂F, methyl, ethyl, propyl, isopropyl, phenyl, —COO(CH₃),—O-methyl and —O-ethyl, as well as pharmacologically acceptable saltsthereof.
 14. Compounds of formula 1 according to claim 12, wherein R³ isa bicyclic 9- to 11-membered heterocycle selected from amongbenzoxazole, benzodioxole, dihydrobenzodioxin, benzodioxin,benzisoxazole, benzothiazole, benzisothiazole, thienopyrimidine,furopyrimidine, thienopyridine, furopyridine, indole, isoindole,quinoxaline, naphthyridine, pyridopyrazine, pyridopyrimidine, quinoline,isoquinoline, benzimidazole,6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine, benzothiophene,benzofuran, quinazoline, indazole, isobenzofuran and pteridine, whichmay optionally be substituted by one or more groups selected from amongF, Cl, Br, CF₃, CHF₂, CH₂F, CN, OH, -methyl, ethyl, propyl, isopropyl,—O-methyl, O-ethyl, —COOmethyl, —COOethyl, SO₂—(CH₃), SO₂—(CH₂CH₃),phenyl, -methylene-phenyl, -ethylene-phenyl, —NH₂, —NH(CH₃), N(CH₃)₂,-methylene-NH₂, -methylene-NH(CH₃), -methylene-N(CH₃)₂, aC₃₋₆-cycloalkyl, a methylene-C₃₋₆-cycloalkyl, a het, a hetaryl,-methylene-hetaryl, and -methylene-het, which may in turn optionally besubstituted by one or more groups selected from among OH, F, Cl, Br,CF₃, CHF₂, CH₂F, methyl, ethyl, propyl, isopropyl, phenyl, —COO(CH₃),—O-methyl and —O-ethyl, as well as pharmacologically acceptable saltsthereof.
 15. Compounds of formula A

according to claim 1, wherein R¹ is H, R² is selected from among

R³ is selected from among

as well as pharmacologically acceptable salts thereof.
 16. (canceled)17. A method for treating diseases associated with the inhibition of PDE4 enzyme in a patient comprising administering to the patient in needthereof a therapeutically effective amount of a compound according toclaim
 1. 18. A method for treating respiratory or gastrointestinalcomplaints or diseases, such as inflammatory diseases of the joints,skin or eyes, cancers, and diseases of the peripheral or central nervoussystem in a patient comprising administering to the patient in needthereof a therapeutically effective amount of a compound according toclaim
 1. 19. A method for preventing and/or treating respiratory orpulmonary diseases which are associated with increased mucus production,inflammation and/or obstructive diseases of the respiratory tract in apatient comprising administering to the Patient in need thereof atherapeutically effective amount of a compound according to claim
 1. 20.A method for treating inflammatory and obstructive diseases such asCOPD, chronic sinusitis, asthma, Crohn's disease, and ulcerative colitisin a patient comprising administering to the patient in need thereof atherapeutically effective amount of a compound according to claim
 1. 21.A method for treating inflammatory diseases of the gastrointestinaltract in a patient comprising administering to the Patient in needthereof a therapeutically effective amount of a compound according toclaim
 1. 22. A method for preventing and/or treating diseases of theperipheral or central nervous system such as depression, bipolar ormanic depression, acute and chronic anxiety states, schizophrenia,Alzheimer's disease, Parkinson's disease, acute and chronic multiplesclerosis or acute and chronic pain as well as injury to the braincaused by stroke, hypoxia or cranio-cerebral trauma in a patientcomprising administering to the patient in need thereof atherapeutically effective amount of a compound according to claim
 1. 23.A pharmaceutical formulation comprising one or more compounds of formula1 according to claim
 1. 24. A pharmaceutical formulation comprising oneor more compounds of formula 1 according to claim 1 in combination withone or more active substances selected from among betamimetics,corticosteroids, other PDE4-inhibitors, EGFR-inhibitors andLTD4-antagonists, CCR3-inhibitors, iNOS-inhibitors and SYK-inhibitors.